pharmacodynamic aspects of modes of drug administration for optimization of drug …. 1999... ·...
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PHARMACODYNAMIC ASPECTS OF MODES OF DRUG
ADMINISTRATION FOR OPTIMIZATION OF DRUG
THERAPY
Amnon Hoffman, David Stepensky
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew
University of Jerusalem, P.O.B. 12065, Jerusalem 91120, Israel.
Fax: +972-2-6436246
Email: [email protected]
Abstract:
Due to various pharmacodynamic properties such as the nonlinearity of the
concentration-effect relationship, activation of feedback homeostatic mechanisms, induction
of pharmacodynamic tolerance etc. administration of the same dose of drug by different
modes is expected to produce different outcomes. This review clarifies the theoretical and
practical aspects of the impact of different modes of drug administration on the magnitude of
response, and hence on therapy outcomes. It discusses how the interrelationship between the
pharmacodynamic properties and the drug input function affect the magnitude of response. To
demonstrate this special dimension of drug therapy, relevant pharmacodynamic data was
obtained for drugs with different therapeutic applications, including antibiotics, analgesics,
diuretics, anti-cancer, anti-ulcer, antiinflammatory, anti-hypertensive, lipid-lowering anti-
parkinsonian, and immunosuppressive drugs. These examples provide guidelines for
implementing the role of the mode of drug administration (including rate, schedule and route
of drug treatment) during drug development or optimization of drug therapy.
Keywords: pharmacodynamics, pharmacokinetics, mode of drug administration, delayed
action preparations, tolerance.
2
1. Introduction
The technological, physicochemical and engineering knowledge for the development of
drug delivery systems has now reached the stage where it provides a very wide selection of
routes, sites, modes and rates of administration of a drug. To use these capabilities rationally,
it is necessary to determine the optimum input pattern of the drug (in terms of efficacy, safety,
convenience and economics) for a particular indication and target population.
By now, it has been established that the development of a drug delivery system (DDS)
should comply with pharmacokinetic considerations, including aspects of absorption,
presystemic biotransformation, distribution, systemic elimination and metabolic fate. In
general, the development of DDS was based on a simplified assumption of a direct
relationship between drug concentration in the blood and magnitude of response.
Accordingly, the basic philosophy behind the development of sustained release (SR)
formulations is to reduce fluctuation in drug response by minimizing fluctuations in systemic
drug concentrations. However, in most cases, the concentration-effect relationship (i.e.
pharmacodynamics) is non-linear. Thus, similar magnitude of fluctuations in drug
concentration at different concentration ranges are likely to cause dissimilar fluctuations in
the magnitude of response.1,2 Consequently, the input function may affect profoundly the
magnitude of drug effect(s) and has to be taken into consideration for optimization of drug
treatment.
2. The pharmacodynamic profile
2.1 Relationship between fluctuation in drug concentrations and
magnitude of response
The mathematical correlation between drug concentration (C) and the intensity of effect
(E) is most commonly described by sigmoid Emax model (see Figure 1):
nn
n
0 CCCmax
50
+ Ε ⋅ Ε
+ Ε = Ε
where E0 is the baseline effect, Emax, the maximal effect, EC50, the drug concentration that
elicits 50% of the maximal effect (i.e., the measure of drug potency), and n, shape factor
which determines the slope of the curve. The value of n has no clear physiological meaning,
but it is thought to evolve from the heterogeneity of concentration-effect properties of the
3
individual effector units (such as individual effector cells or channels).3
Different concentration ranges along the pharmacodynamic profile are shown in Figure
1. It can be seen that a certain degree of fluctuation in drug concentration (∆C) at different
zones elicit different degrees of change in magnitude of drug effect (∆E).2 Alterations in drug
concentration within E0 zone or Emax zone do not affect the magnitude of drug effect. Within
EC50 zone, ∆E is directly proportional to ∆C (or more specifically to ln∆C). In contrast,
fluctuations in drug concentration in Low E zone and High E zone produce non-proportional
change in ∆E. For instance, for n=1 a two-fold increase in drug concentration produces an
80% increase of drug effect at low E zone, a 46% increase at the EC50 zone, and only a 10%
increase at high E zone.
The sigmoidicity of the pharmacodynamic profile has a profound influence on the
magnitude of ∆E/∆C and on the width of a specific concentration zone. Generally, when n <
1, a shallow pharmacodynamic profile is observed resulting in moderate attenuation in
magnitude of effect even for large degrees of ∆C. Consequently, a high increase in drug
concentrations is needed in order to proceed from the minimal to maximal extent of drug
effects. For such a pharmacodynamic profile, SR formulations that minimize fluctuations in
drug concentration are less important. On the other hand, for n > 1, the resulting
pharmacodynamic curve is steep and is characterized by high affectability of response
intensity to a change in drug concentration. For n > 5 all-or-none response is observed and
small increment in drug concentrations near the EC50 region produces rise from E0 to Emax.
For these drugs the range between EC50 and the minimal concentration required to elicit Emax
(ECmax) is very narrow and it is extremely important to maintain drug concentration above
ECmax (e.g., levodopa – see specific section).
2.2 The impact of the rate of administration on the magnitude of
drug effect
The fact that pharmacokinetic processes are usually linear but in most cases the
concentration-effect relationship is nonlinear leads to profound impact of the drug input
function on the extent of the pharmacologic response. To illustrate this issue, a simulation of
pharmacokinetic and pharmacodynamic behavior of the drug following administration of the
same total dose at different rates was performed (Figure 2). The concentration vs. time
profiles were based on a one compartment model by applying bolus mode of drug
administration or constant infusion of the same total dose over 2, 4, 8 or 12 hours. The effect
vs. time data was produced by linking the concentration-time data to a sigmoidal Emax model
4
(Emax = 100% and EC50 = 0.05 mg/L) with different shapes (n = 0.5, 1, or 4). The impact of
different parameters on the magnitude of drug action may be estimated by comparing AUEC
values (area under effect curve) or by using an efficiency factor (EF = AUEC / AUC).4
The simulations show that the magnitude of effect is highly influenced by the rate of
drug administration. Prolongation of the administration time increases AUEC values by
several-fold. The magnitude of effect depends also on n value, particularly for lower rates of
drug administration. It can be seen that an increase in value of n from 1 to 4 increases the
effect (i.e., AUEC) by approximately 20% for the 4-h and the 8-h infusion regimens. The
opposite tendency occurs by prolongation of the infusion time to 12-h because Css values
drop below EC50 level.
Generally, the overall efficiency value of a certain mode of administration is a function
of the time that drug concentrations are maintained at the different concentration zones along
the pharmacodynamic curve. For the sigmoidal Emax model, maximum efficiency is
produced if the drug concentrations are continuously kept in the high E zone.4 Thus, for bolus
mode of administration relatively large AUC values can be associated with low AUEC value,
particularly if the peak drug concentrations happens to be several-fold higher than ECmax. In
this case, a sustained drug administration that prolongs the time spent over ECmax will
produce higher EF values (e.g., see section on beta-lactam antibiotics). On the other hand, if
Css value produced by continuous administratiis within the E0 zone, the overall efficiency
would be negligible in comparison to a bolus administration of the same dose.
It can be concluded that in most cases the magnitude of drug effect is dependent on the
mode of drug administration. The overall drug efficiency is dependent on the interrelationship
between several pharmacokinetic and pharmacodynamic parameters, including the dose and
rate of administration and the pharmacodynamic profile of the specific response. Simulations
showing the relationship between the drug dose and magnitude of drug effects in the sigmoid
Emax model were presented recently.5
3. Time-dependency of pharmacodynamic effects
It should be taken in account that temporal alterations in concentration-effect
relationship may occur, influencing the efficiency factor following drug administration.
Apparent time-dependency of the drugs pharmacodynamic parameters may result from a
delay between the pharmacokinetic and activity time course, or because of intrinsic alterations
of pharmacodynamic parameters.
5
3.1 Hysteresis in the concentration-effect profile
In some cases, the pharmacologic response is delayed in relation to the kinetics of the
appearance of the drug in the blood and a counter-clockwise hysteresis is present in the
concentration-effect relationship.6 In certain cases, the reason for this outcome is a slow
equilibration between drug concentration in the systemic circulation and peripheral site(s) of
action. Consequently, a non-steady state effect-concentration relationship is produced, leading
to time-dependent changes in pharmacodynamic parameters. In order to elicit a certain
magnitude of effect, higher plasma concentrations are required at the beginning of drug
administration, and lower concentrations are needed once the drug is distributed to the
biophase. The magnitude of hysteresis is minimized by a slower rate of drug administration,
that reduces Cmax concentrations in the systemic circulation. Delayed response may also
result from the production of active metabolites, indirect pharmacodynamics due to time-
consuming signal transduction (accounting for delay between receptor binding and measured
effect), etc.
Several mathematical methods have been developed to overcome temporal discrepancy
in concentration-effect relationship and to estimate the intrinsic pharmacodynamic
parameters. Collapsing the hysteresis in the concentration-effect curve is a practical approach
that utilizes the indirect link model developed by Holford and Sheiner.7
3.2 Direct and indirect response
Discrepancy between the time courses of concentration and effect may be related to
indirect mechanism of drug action. This is true, for instance, when the observed drug response
is secondary to a previous, time consuming synthesis or degradation of endogenous bioactive
substance.8 Four basic pharmacodynamic models of indirect effects were developed by Jusko
et al, and were applied for numerous drugs, including hormones, diuretics, etc.9 Effect of the
drug input profile on the overall efficiency of drug effect in these indirect models have been
discussed thoroughly in recent review.4 In this work the concentration vs. time profiles of
low, medium and high drug doses were simulated for a one compartment model applying
bolus mode of drug administration or constant infusion over 6, 12, 24 or 72 hours. The
pharmacodynamic response was generated using four basic models of indirect effects (I-
inhibition of synthesis of endogenous substance, II-inhibition of degradation, III-stimulation
of synthesis, and IV-stimulation of degradation). The effect of the rate of administration and
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drug dose on magnitude of pharmacologic effect is presented in Figure 3.4
It may be seen that slower rates of drug delivery improve the efficiency of the same
total dose. A maximal influence of the rate of drug delivery on the pharmacological response
was observed after the high dose. The influence of the infusion rate was the greatest for
Model II. While models I, III, and IV produced in a maximum of about 4-fold increase in
efficiency factor for continuous infusion compared to bolus mode of administration, model II
resulted in a 7-fold increase.
The results of the present simulation indicate that the pharmacodynamic efficiency is
dependent on the relationship between the target drug concentrations and IC50 values. For
relatively high drug doses, slower rates of drug delivery produce higher AUEC values and
comparable maximal effects (Emax). Further reduction in the rate of input lowers the
maximal effect, while higher AUEC values are attained. If additional attenuation in drug
release produces target concentrations that are below IC50, both maximal effect and
pharmacodynamic efficiency are reduced.
3.3 Tolerance phenomenon
The concentration-effect relationship of certain drugs is affected by continuous
exposure to the drug. Thus, due to changes that occur at the cellular level (such as gradual
reduction in the receptor density (down-regulation)), larger concentrations may be required to
maintain the same magnitude of effect over time, producing a tolerance phenomenon.
Evolvement of tolerance was observed for several drugs, including anticonvulsants, anti-
inflammatory drugs, amphetamines, barbiturates, benzodiazepines, caffeine, cocaine and
other CNS stimulating drugs, digitalis (heart failure), dopamine agonists, ethanol, indirectly
acting sympathomimetics, nicotine, organic nitrates, opiates, vasodilating drugs (heart
failure).10 It should be noted that if the pharmacologic responses of the drug are due to
interaction with different types of receptors, tolerance may develop for some, but not
necessarily for all drug effects. Magnitude of tolerance is related to the drug input function
(i.e., is time- and exposure-dependent) and is enhanced following slow drug input.11 In
general, the influence of the mode of administration is more substantial in the case of acute
tolerance development, such as in the case of organic nitrates (see specific section) which
indicates that SR mode of administration should be limited, and is less notable in those cases
where tolerance development is slow (e.g., levodopa - see specific section).
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3.4 Pharmacodynamic alterations due to activation of homeostatic
responses
Activity of many of the biochemical and physiological processes in the living body is
maintained within a certain limited range by means of feedback loop systems. In such a way
the body protects itself from drastic changes that would jeopardize the homeostasis. If the
homeostasis is altered due to pharmacological intervention, powerful feedback mechanisms
are activated, decreasing the magnitude of drug effect. The extent of activation of feedback
mechanisms is highly dependent on the rate of drug administration. While a bolus
administration may provoke counter activity, slow drug input may affect the body without
acute triggering of homeostatic responses.12
The ‘off response’ should also be taken into account for drugs that affect the body
homeostasis. Abrupt termination of drug input in such case may result in potentially
dangerous increase in drug effects (rebound activity). This phenomenon is specifically known
for antihypertensive drugs.13
4. Therapeutic and toxic effects
Almost all drugs possess multiple pharmacologic activities that are regarded as
therapeutic or side effects. It is important to understand that each of the pharmacologic effects
of the drug has its own pharmacodynamic profile. In order to optimize drug treatment the
pharmacodynamic profiles of both therapeutic and adverse drug effects should be taken into
account. As was discussed previously, for a particular pharmacodynamic profile, extent of
drug effect is profoundly dependent on the drug input function. Thus, optimization of drug
treatment must be applied to the differences in the pharmacodynamic profiles for different
drug effects, based on the knowledge of the drug’s pharmacodynamics, applying dosing
schedules with a higher ratio of resulting therapeutic/toxic effects.
In the case that different types of drug receptors are responsible for therapeutic and side
effects, selective activation/inhibition of receptors may be achieved by applying SR
formulations of the drug and producing a relatively narrow range of target drug
concentrations. General considerations concerning impact of mode of administration and dose
on selectivity of pharmacologic response were discussed recently by Hochhaus and
Derendorf.5
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5. Measurement of pharmacologic effect: The use of surrogate
endpoints as indices of therapeutic outcomes
In some cases, such as anti-cancer and immunosuppressive treatment (see specific
chapters), the magnitude of therapeutic effects and clinical outcome following the drug
treatment are not readily accessible. In this case, surrogate endpoints may be applied to
measure the biological activity and to adjust the treatment schedules. The optimal surrogate
endpoint should have the potential to yield unambiguous information about differential
treatment effects on the true endpoint. The relationship between surrogate marker and the
clinical outcome should be well established, both qualitatively and quantitatively, through
relevant epidemiological studies in order to estimate the expected clinical benefit. However,
the convenience of relying on biological markers on one hand and the substantial difficulties
in quantifying clinical end points and outcomes that are delayed in connection with changes in
the disease process, have led researchers to utilize surrogate markers, sometimes without
validation of their appropriateness. As noted recently by Colburn, although surrogate markers
can expedite the delivery of new therapeutic drugs to the market, if the marker is applied
inappropriately, it can prolong the development process and discourage their use.14 For
example, use of CD4 counts as surrogate markers for prolonged survival of patients with
human immunodeficiency virus (HIV), or reduction in premature ventricular contractions to
predict prolonged life expectancy have proven to be invalid.15,16
The issue of surrogate markers is raised here because in many cases they are being used
as a graded measure of pharmacological effect, which enables one to produce a reasonably
good pharmacokinetic/pharmacodynamic model of the kinetics of drug action. The important
issue is to clearly distinguish between those surrogate markers which are validated from those
that are associated with drug activity but do not provide sound indication about the real
clinical outcome.
6. From theory to practical examples: Pharmacodynamic
considerations in treatment of specific diseases
Controlled release (CR) dosage forms of medications have become relatively
prevalent in medicine today because of their ability to improve compliance and, perhaps, to
increase efficacy.17 CR formulations were developed according to the concept that ‘flatter is
better’, and formulation design tended to minimize fluctuations in drug blood concentrations.
9
As discussed above, this concept has many exceptions that evolve from the pharmacodynamic
characteristics of the drug and the mode of administration. The available information about
these factors is rather limited, and is only recently gaining momentum. In certain fields the
pharmacodynamic considerations have been thoroughly studied and have led to practical
modifications in mode of drug administration. For example, this has been seen in SR
nifedipine and other anti-hypertensive preparations, and hormonal therapy with gonadotropin
releasing hormone (GnRH). For other drugs, the available information about the impact of
mode of administration on magnitude of response (of both desired and adverse effects), and
hence, on therapy outcome, is scarce. In many cases, pharmacodynamic information that is
relevant for understanding the impact of the input function-response relationship is reported
indirectly or provides only partial or inconclusive knowledge. The goal of this review is to use
the available information in order to draw the picture of the influence of the mode of
administration on drug effect(s) in several clinical fields. Selected examples provide
guidelines for implementing this dimension of mode of drug administration (including rate,
schedule and route of drug treatment) during drug development or for optimization of drug
therapy.
7. Pharmacodynamics of antibacterial drugs
The major parameters used to quantify the effect of antimicrobial drugs are the minimal
inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC). Although
these parameters are good predictors of the potency of the drug-microorganism interaction,
they do not provide any information on the kinetics of action of the drug. For instance, the
MBC value does not provide information on the rate of bactericidal activity and whether this
rate can be enhanced by increasing antimicrobial concentrations. Similarly, MIC does not
provide any information about the persistent activity of the antimicrobial agent that remains
following exposure to the drug. These persistent effects include the postantibiotic effect
(PAE), postantibiotic sub-MIC effect (PAE_SME) and the postantibiotic leukocyte
enhancement (PALE).18 The degree of PAE and PAE_SME, that are very different for each
class of antimicrobial drugs (and for each specific drug-bacteria interaction), provide a better
understanding of the kinetics of drug action, thus furnishing a rational basis for determining
optimal dosage regimens for various human infections.
Antibiotics can be divided into three categories based on their pharmacodynamic
properties, including both their bactericidal activity and their persistent effects.19 The first
group of drugs (Category I) exhibits minimal concentration-dependent killing and produces
10
short term or no persistent effect with most bacteria. The killing rate of these antibiotics
saturates at concentrations of around four to five times the MBC. Thus, high concentrations
will not kill bacteria faster than lower concentrations. Furthermore, bacterial regrowth starts
very soon after serum and tissue concentrations fall below MIC. Penicillins, cephalosporins
and aztreonam exhibit this time course of antimicrobial activity. The second group (Category
II) is characterized by concentration-dependent killing over a wide range of concentrations,
and by prolonged persistent effects. The higher the drug concentration, the greater the rate and
extent of bacterial killing. This category includes aminoglycosides, fluoroquinolones and
metronidazole. Category III contains drugs such as vancomycin, clindamycin and macrolides
that demonstrate minimal concentration-dependent killing; however, they have prolonged
persisting effects.
7.1 Beta-lactam antibiotics (Category I)
7.1.1 Pharmacodynamic rationale for continuous adminis ration of beta-lactam
antibiotics
t
In vitro studies of the pharmacodynamics of beta-lactam antibiotics have shown that
killing of bacteria, in particular Gram-negative aerobic rods, is slow, time dependent, and
maximal at relative low concentrations.20 Further elevation of the dose is not associated with
increased bactericidal potency.21 It had been also suggested that at concentrations much
greater than the MIC a paradoxical pattern may occur, i.e., a decrease in bacterial kill
potency.22,23 These findings have led to the hypothesis that continuously maintained
concentrations above a certain level, related to the MIC for the specific pathogen, would be
more efficacious than the high peak and trough concentrations obtained with an intermittent
dosing regimen. Efficacy studies in laboratory animals are in agreement with these in vitro
findings. It was found that in order to obtain the same efficacy the daily doses have to be
eight-fold higher during intermittent infusion regimens than with continuous infusion.22
Other studies have shown that the percentage of survival of the animals increased linearly
with the frequency of dosing and time over the MIC but not with other pharmacodynamic
parameters.24 In addition to the preclinical findings, several clinical efficacy studies
corroborate this concept; however, these are still scarce. Schentag et al have shown a
significant relationship between time to eradication of Gram-negative pneumonia and time
over MIC.25 Weinstein et al examined the relationship between beta-lactam concentrations at
trough and the success of therapy in patients with acute and chronic osteomyelitis.26 It was
found that maximum efficacy with beta-lactam antibiotics in humans appeared to be
11
dependent on maintaining levels above the MIC of the infecting organism for the majority of
the dosage interval. The few randomized trials that have compared the efficacy of the beta-
lactams given by continuous infusion vs. intermittent administrations also support this
conclusion.
Exposures of staphylococci, streptococci or enterococci to different beta-lactams are
consistently followed by PAEs of several hours duration.21 This persistent suppression of
gram-positive cocci growth enabled the development of intermittent dosing regimens for
these drugs. Traditionally, intermittent intravenous infusions or intramuscular injections have
been considered to be the optimal dosing regimens that worked reasonably well in clinical
practice. However, due to the increasing number of immunocompromised patients, the rising
incidence of gram-negative infections, and the availability of improved intravenous drug
delivery systems, new strategies have been introduced for improving antimicrobial therapy
with beta-lactams. These strategies apply continuous infusions of these drugs to provide
improved patient outcome with reduced doses of drug.22
In summary, the goal of the dosage regimen of beta-lactam drugs should be to prevent
the drug-free interval between doses from being long enough for the bacterial pathogen to
resume growth.
7.1.2 Potential disadvantages associated with continuous administration of beta-
lactams
It is conceivable that if the infection is located at a site from which the antibiotic is
eliminated by a rate-limiting active transport, intermittent dosing would result in higher
concentrations at the site of infection than would continuous administration (e.g., infections in
the eye or cerebrospinal fluid). However, such a scenario is limited to a particular range of
antibiotic concentrations and then would apply only for those beta-lactams that are handled by
such mechanisms.24
Another situation is in a case where the antibiotic drug is eliminated from the site of
infection due to beta-lactamases, again with a rate-limiting step. For example, while an
antibiotic was diffusing to the center of an abscess, degradation by beta-lactamase-producing
bacteria could degrade it, thus producing antibiotic concentrations near zero during
continuous administration.
It was found that not all beta-lactam-bacteria interactions follow the rule of non-
concentration-killing efficacy dependency. For instance, Onyeji et al have showed that
cefaclor exhibited a marked inoculum effect against four pathogens studied, and that there
12
was concentration dependent killing at a large inoculum.27
With continuous infusion, a delay in drug equilibration to tissues occurs because of the
lag time required to reach effective steady state concentrations in serum. However,
administration of a loading dose prior to continuous administration would ensure the rapid
onset of antibacterial activity.
Another pharmacodynamic concern is a situation where continuous exposure to
antimicrobial concentrations is only slightly over the reported MIC. Thus, specific sub-
populations of resistant organisms that are typically not detected by MIC testing could grow.
Nevertheless, the development of resistance has not been found in any of the clinical trials
reported until now, probably because of the contributing activity of the immune system.
7.1.3 The target therapeutic concentration
Several investigators have proposed, based on in-vitro experiments, that a maximum
effect is reached at 4x MIC for the target bacterium.24 Preclinical investigation clarified that
the target ‘therapeutic concentration’ depends on the status of the immune system. For
example, serum ceftazidime concentration needed during continuous infusion to obtain 50%
efficacy in normal rats was between one-sixth and one-third the MIC, for the infecting K.
pneumoniae, depending on the severity of the infection. However, the concentration needed to
obtain 100% efficacy (ED100) was dependent not only on the severity of infection but also
whether the animals were leukopenic or not.24
7.1.4 The required time over MIC (T>MIC)
Craig has summarized all the available data from the literature that use mortality as an
endpoint and in which animals infected with S. pneumoniae were treated with penicillins or
cephalosporins.28 The duration of time that the serum level needs to be above the MIC to
ensure efficacy is shown in Figure 4. It can be seen that the mortality was virtually 100% if
serum levels were above MIC for 20% or less of the dosing interval. In contrast, as soon as
T>MIC was 40% - 50% of the dosing intervals or higher, bacteriologic efficacy was 90 to
100%. Similar results were found in clinical studies that assessed bacteriologic cure in otitis
media.29 The findings indicates that if serum levels are above the MIC for 40% to 50% of the
dosing interval, a bacteriologic cure of over 90% is obtained.
7.1.5 Parenteral versus oral therapy with beta-lactam antibiotics
13
The decision to use parenteral or oral therapy to treat an infectious disease has
traditionally depended primarily on the severity of the infection. It is often assumed that if the
patient with an infection is sick enough to be hospitalized, the patient is also sick enough to
receive parenteral antibiotics. The enhanced understanding of the concentration-activity of the
antibacterial efficacy has clarified that proper therapy can be achieved with oral
administration of antibiotic drugs. According to the rationale discussed above, the preferred
parenteral dosing strategy for therapy with beta-lactam antibiotics is continuous infusion.30
However, this approach has certain limitations, of which the most problematic issues are the
patient inconvenience due to decreased mobility, increased risk of bacteremia due to
intravenous line - infection, increased costs due to necessity for hospitalization and the need
for trained medical personnel for parenteral antibiotic administration. Oral therapy can replace
part of the parenteral antibiotic therapy.31 The major trend in oral beta-lactams has been to
find new drugs that have increased potency against gram-negative pathogens and longer half-
lives. However, several pharmaceutical approaches can also be used to prolong T > MIC. The
most obvious approach would be administration of larger doses that produces a longer
duration of T > MIC (as illustrated in Figure 5). This approach can be used for a beta-lactam
with elimination half life of 1 hr, such as penicillin V-K, that is an inexpensive drug, and
whose elevated concentrations are not associated with severe adverse reactions. However, a
considerably larger total daily dose is needed to achieve the same magnitude of T > MIC in
comparison to continuous administration.
Another approach to prolong T > MIC for beta-lactams is to develop an oral controlled
release formulation, which provide continuous administration of the drug from the gut to the
systemic blood circulation. Due to flip-flop pharmacokinetics of the sustained release
formulation, the apparent elimination half-life of the drug is extended. We have demonstrated
this approach with a hydrophilic matrix formulation of amoxicillin.32 This beta-lactam
antibiotic had pharmacokinetic properties that are similar to other drugs from this category,
including short elimination half life, and active absorption that is limited to the upper parts of
the gastrointestinal (GI) tract. Prolongation of T > MIC for these drugs following oral
administration (in vivo) is limited by the narrow absorption window.33 To overcome this
pharmacokinetic limitation the controlled release matrix tablet was designed to release 50% of
its content within 3 h, followed by a constant release rate for about 8 h.34 The rapid onset of
drug release was designed to provide an initial ‘loading dose’ and to maximize the absorption
phase in those parts of the intestine in which amoxicillin is actively absorbed by a carrier-
mediated process.35,36 The in vivo evaluation of the new formulation revealed that the extent of
absorption of the new formulation is not much different than that of a regular soft gelatin
14
capsule formulation. Furthermore, the time required to obtain therapeutic concentration (‘onset
time’) was found to be identical for the two formulations. However, T > MIC as well as T >
4.MIC of the drug against susceptible pathogens was found to be maintained for a significantly
longer period.
7.2 Pharmacodynamic rationale for pulse dosing of antibiotics with
concentration-dependent bacterial killing properties (Category II)
The drugs in this category are characterized by concentration-dependent killing over a
wide range of concentrations and by prolonged persistent effects. The goal of a dosage
regimen for these drugs is to maximize concentration. The magnitude of the peak level and
the AUC in relationship to MIC would be the important determinants of efficacy for these
drugs. Wide dosing intervals are also possible because these drugs induce prolonged PAE.
Sub-MIC concentrations and the presence of leukocytes can further prolong the PAE. These
preferred dosing strategy were found in-vitro and in preclinical studies and were partially
confirmed in clinical studies.
7.2.1 Pharmacodynamics of fluoroquinolones
The 24-hr AUC/MIC ratio is the parameter that best correlates with the efficacy of
fluoroquinolones as shown in Fig. 6.18,37 When tested for ciprofloxacin, this parameter was
better than the peak drug concentration and considerably better than T > MIC, which needed
to exceed the MIC for about 20% of the time interval to obtain any bacterial killing. In animal
infection models, the magnitude of the 24-hr AUC/MIC required to produce a bacteriostatic
effect is ~ 35.37 This value implies that the AUC averages ~ 1.5 times the MIC over 24 hr
period (i.e., 1.5 x 24 =36). This value is independent of the dosing interval, the
fluoroquinolones used, and the site of infection.18,38 It was found in experimental animal
infections and in clinical trails that the fluoroquinolones concentration in serum need on
average about 4 times the MIC in order to ensure bactericidal activity and patient cure. In vivo
preclinical studies confirmed the PAE of these drugs.
The development of the fluoroquinolones is considered to be the major advance over
the past decade in oral antimicrobial therapy due to their enhanced activity against gram-
negative bacilli. Twice a day dosing, by either oral dosing or intravenous administration
produce 24-hr AUC/MIC values that are considerably higher than 125 for various bacterial
species.
15
7.2.2 Once a day aminoglycoside administration
There appears to be a general consensus that pulse dosing of aminoglycosides offers the
following advantages: i) relatively easy, straightforward initial dosing; ii) enhanced efficacy
due to higher peak levels; iii) enhanced safety due to shorter effective exposure time; iv)
convenience for both patients and nurses; v) likely on-time administration; vi) a much
reduced need for serum aminoglycoside levels monitoring (reduced cost); vii) facilitation of
drug administration through home care services (reduced cost).
While in preclinical investigations the 24-hr AUC/MIC ratio better correlated with
therapeutic efficacy than peak/MIC ratio, the opposite was found in the major clinical trials.39
To achieve a clinical response of >90% the peak concentration should exceed the MIC by 8–
10 fold. The once a day regimen that produces such elevated peak concentrations can also
reduce the rate of emergence of aminoglycoside-resistant mutants during therapy.40 This is
because the initial exposure of the microorganisms to aminoglycosides down-regulates
subsequent uptake of drug, thus higher MICs are exhibited for several hours.41 Therefore, the
larger time intervals that result from once-daily dosing regimen of the aminoglycosides enable
this effect to dissipate until next dosing. This, in addition to the prolonged PAE (2-8 hr) of
these drugs (which provide continued suppression of bacterial growth despite the decline of
the antimicrobial concentration to zero), augments the rationale for increased intervals
between doses (i.e. once daily vs. multiple daily dosage regimens).
The pharmacodynamics of aminoglycoside toxicity also corroborates once daily dosing
of these drugs. The mechanism of aminoglycoside nephrotoxicity involves an absorptive
influx at the proximal convoluted tubule cells that is mediated by a low affinity, high capacity
mechanism that can be saturable. Thus the uptake into the kidney is more efficient with low
sustained concentrations than with high intermittent concentrations. Several studies have
showed that the onset of nephrotoxicity is delayed for several days when the drug is
administered once daily.42 Animal studies that have examined ototoxicity show that the
degree of the cochlear damage is more related to the total daily dose of the aminoglycoside
rather than the frequency of administration. Hence, saturation of cochlear cells may play a
role in determining ototoxicity.43
Multiple meta-analysis studies that assessed the impact of mode of aminoglycoside
administration on therapeutic outcomes suggest a small, non significant trend towards better
efficacy and lower toxicity with once-daily regimen.44 However, it should be noted that not
in all situations once daily dosing would be a better choice than traditional intermittent dosing
regimens.43
16
7.3 Optimal dosing regimens of Category III antibiotics
The main pharmacodynamic parameter for drugs in this category is also the duration of
exposure. However, the relatively long elimination half-life together with persistent effects
allows drug levels to fall below the MIC for considerable portion of the dosage interval. Thus,
due to their unique pharmacokinetics and pharmacodynamics, the therapeutic outcomes
following therapy with these drugs is not affected by the mode of administration. For
instance, the optimal dosing method for vancomycin may be the one that achieves the lowest
AUC while concentrations are maintained above the MBC.45
7.4 Targeted antibiotic treatment by SR drug delivery systems: the
case of periodontitis
The clinical manifestation of periodontitis is the formation of a deeper space between
the teeth root surface and the opposing periodontal tissue. This crevice is termed a periodontal
pocket and its depth usually exceeds 5 mm. The anatomic configuration of the periodontal
pocket is an ideal habitat for microflora that is mainly composed of gram-negative bacteria
(mostly anaerobic). Collagenase and other enzyme that originate from the bacteria can destroy
the connective tissue of ligaments, while exotoxins evoke an inflammatory reaction. When
mechanically cleaning methods to improve oral hygiene fails, a chemotherapeutic approach
may be applied. Systemic administration has been useful in treating periodontal pockets, but
repeated, long term use of systemic antibiotics is fraught with potential danger including
resistant strains and superimposed infections. Therefore, the periodontal pocket is an excellent
example for localized infection site for which local administration of a drug by SR delivery
system provides an extremely useful solution. The important factor in the success of this
treatment is the ability to control and the release of the drug, thereby maintaining high intra-
pocket drug concentrations with very low plasma concentrations.
Intra-pocket delivery systems were found to be very effective clinically. The selection
of the antibiotic agent for these SR periodontal delivery systems has to be guided according to
the following principles. Since the amount of drug that can be placed in the periodontal
pocket is limited, the drug has to be highly specific against the periopathogenic bacteria. It
should not cause the development of resistant bacterial strains, and should not affect the soft
tissue of the pocket. So far, antiseptic agents, including chlorhexidine, cetylpyridinium
chloride and parabens on one hand, and antibiotics such as tetracycline, minocycline,
doxycyline, and metronidazole, on the other hand, have provided very effective control of the
periodontal microflora and significant reduction of the pocket depth (see Steinberg and
Friedman for a recent review46).
17
The same principles of local SR delivery of antibiotics that were noted above for the
treatment of periodontitis can be applied for other localized infections particularly for low-
perfused sites.
8. Anticancer drugs
Anticancer drugs are characterized by a low therapeutic index and a high extent of
intra- and inter-patient variability in pharmacokinetics and drug effects. Pharmacokinetic
studies indicate highly variable absorption, tissue distribution and elimination for most
anticancer drugs. Several–fold differences in drug clearances within a homogeneous patient
population have been observed for major anticancer drugs, including methotrexate, etoposide,
doxorubicin, cylophosphamide, etc.47 The extent of drug effects is also variable and depends
on mode of drug administration, tumor- and host-related factors. For certain tumors, the
chemosensitivity to certain agents is related to immunophenotype, tumor localization,
proliferative potential, and may be a subject to circadian variability.48,49 Figure 7 illustrates
variability in doxorubicin effect on human bladder tumors applying ex-vivo testing of drug
activity. In this study, a 35-fold variability in superficial bladder tumor chemosensitivity to
doxorubicin was observed, as opposed by only 4-fold variability in tissue pharmacokinetics.50
Thus, to optimize clinical outcome, the patient status should be assessed frequently and drug
dosing should be appropriately adjusted.
Choice of treatment regimens with anticancer drugs in most cases is based on
pharmacokinetic principles and clinical empiricism. This is mainly because the desired effect
(i.e., a reduction in tumor size or amount of tumor cells) is not readily detected and is not
applicable as a measure of clinical outcome. Generally, several types of pharmacokinetic or
pharmacodynamic markers can be applied for monitoring cancer patients. In certain cases, the
extent of main adverse effects (myelosuppression and gastrointestinal toxicity) appears to be
related to the systemic drug exposure, and monitoring of adverse effects may be applied for
adjustment of treatment protocols in the specific patient. It should be mentioned that a
temporal discrepancy exists between exposure time to the drug and the measured drug effects
and clinical outcome.
Anticancer drugs are seldom used as single therapy due to variability of tumor response
and elevated risk of emergence of resistance. When combination chemotherapy is applied,
pharmacodynamic relationships for individual anticancer drugs can’t be readily resolved.
Common use of support medications (i.e., antiemetic drugs, growth factors, protective agents,
etc.) and multiple courses of drug treatment further complicate the comparison between
18
different clinical settings and study of the drugs’ pharmacodynamic profile.
Due to the outlined reasons, little is known about the
pharmacokinetic/pharmacodynamic relationships of therapeutic or toxic responses of
anticancer drugs. Most pharmacokinetic/pharmacodynamic studies have focused on finding
correlations between the drug exposure and the extent of response following certain schedules
and modes of administration of the anticancer drug. Theoretical analysis suggests that the
pharmacodynamic profile of therapeutic response is related to the mechanism of action of a
specific drug, i.e. different profiles are expected for cell-cycle-specific or cell cycle-non-
specific anticancer drugs.51,52 If a drug’s cytotoxic activity is independent of cell growth
cycle (cell cycle-non-specific agents), a direct relationship is expected between the drug
exposure (i.e., AUC over a certain threshold concentration) and the response and the
sigmoidal Emax model may be used to describe the pharmacodynamic profile. In this case,
the total cytotoxic effect of a given dose of drug is independent of the schedule of
administration. This is not true for cell-cycle-specific agents whose mode of action is related
to the formation of active metabolites or accumulation of intracellular drug complexes. For
such drugs, the administration schedule may profoundly affect the extent of response. That is
because the response is mostly related to the duration of exposure above a threshold
concentration than to peak drug concentrations.
The goal of anticancer therapy is to produce the maximal therapeutic response while
producing acceptable toxicity. For a particular drug this may be accomplished by using the
difference between the pharmacodynamics of the therapeutic and toxic effects. The focus of
this review is mainly on optimization strategies of mono-therapy with selected anticancer
drugs, and on the impact of the mode of administration (dosing schedule, dose, and route of
administration) on the clinical outcomes.
8.1 Cell cycle-non-specific agents
8.1.1 Doxorubicin
The anthracycline doxorubicin is widely used in the treatment of both hematologic
malignancies and solid tumors. Doxorubicin is a cell cycle-non-specific agent, and the extent
of therapeutic response for a given dose should not be dependent on the schedule of
doxorubicin administration.52 However, doxorubicin cardiotoxicity appears to be
administration rate-dependent. A 24-hr infusion resulted in significantly higher cardiotoxic
effect in comparison to a 48- or 96-h infusion, whereas the incidence of myelosuppression
and mucositis were not affected.51,53 A once-weekly IV bolus administration schedule of
doxorubicin significantly reduces cardiotoxicity as compared with a once every 3 week
19
schedule but still does not affect the magnitude of the cytotoxic effect.54 Thus, the extent of
cardiotoxicity is related to the peak plasma concentrations, and more prolonged modes of
administration are needed to optimize the clinical outcome.
8.1.2 Platinum compounds
Cisplatin and carboplatin are cell cycle-non-specific agents widely used for treatment
of a variety of solid tumors. The major adverse effects of cisplatin are renal, neurologic and
ototoxic. A recent pharmacodynamic study by Nagai and Ogata showed that AUC values
highly correlate with cisplatin induced nephrotoxicity in rats.55 The maximum blood urea
nitrogen (BUN) level served as a marker of nephrotoxicity. The main results of the study are
presented in Figure 8. It may be concluded that an infusion mode of administration produced
2-3-fold less nephrotoxicity, compared to the effect of the same dose administered as bolus. In
addition, duration of exposure above a threshold concentration (AUC > Cmin) was shown to
be linked to the extent of nephrotoxic effect, irrespectively of dose and schedule (see Figure
9). Clinical studies in patients with various types of cancer showed that extent of
nephrotoxicity is mainly correlated with peak concentrations of cisplatin (Cmax),56 and that
slower administration rate results in lower incidence of gastrointestinal toxicity (emesis).57,58
Thus, for cisplatin, the extent of therapeutic activity is largely independent of mode of drug
administration, but continuous dosing schedule should be applied to reduce the incidence of
adverse effects.
The same considerations should apply for other platinum compounds, despite
somewhat different clinical profile. The toxicological properties of carboplatin differ from
that of cisplatin, and its primary dose-limiting toxicity is thrombocytopenia. A significant
relationship was found between area under the curve (AUC) and tumor response,
thrombocytopenia, and leukopenia in patients with advanced ovarian cancer.59 Circadian-
modulated treatment schedule of carboplatin showed no clinical advantage over flat infusion
in patients with advanced cancer.60 In contrast, a clinical study with another platinum
compound, oxaliplatin, showed lower incidence of neutropenia and vomiting in a circadian-
modulated mode of administration to carcinoma patients.
8.2 Cell-cycle-specific agents
8.2.1 Etoposide
Etoposide is cell-cycle-specific drug (late S and early G2 phases) which is highly active
in small-cell lung cancer and lymphoma. The schedule of etoposide administration profoundly
20
influences the extent of drug effects both in vitro and in vivo. Continuous exposure to low
levels of the drug was shown to produce enhanced therapeutic response in comparison to
bolus dosing. For instance, five consecutive daily 2-hr infusions produced partial remission in
89% of patients in comparison to a 10% response in a single 24-hour infusion of etoposide in
patients with small-cell lung cancer.61 The patient survival curve in this study is presented in
Figure 10. The AUC values were identical in the two arms of this study, but the duration of
exposure to low concentrations of drug ( > 1 mg/L) was doubled in the 5-day arm.
Several clinical studies showed that the hematological toxicity of etoposide is
correlated to the systemic drug exposure. For instance, in low-dose etoposide administered
orally to children with solid tumors, the time of exposure above a threshold concentration was
found to be more strongly correlated with neutropenia than other pharmacokinetic parameters,
including dosage and AUC.62 Antitumor activity is generally associated with the maintenance
of lower levels of etoposide than hematologic toxicity. Clark et al found that duration of
exposure to plasma etoposide > 3 mg/L is predictive of a nadir neutrophil count and > 2 mg/L
is predictive of a nadir WBC count.63 Then the same dose of etoposide was administered as 8
daily 75-minute infusions or 5 daily 2-hour infusions to patients with small-cell lung cancer,
higher hematologic toxicity was found for 5-day arm of the study due to prolonged periods of
time of higher exposure to etoposide.
In addition to schedule dependency of drug effects, clinical treatment with etoposide is
complicated by a high degree of inter-patient pharmacokinetic variability. Several clinical
conditions associated with elevated risk of adverse effects were identified, including patients
with impaired renal function, low serum albumin concentrations, or highly elevated liver
enzyme values.64 Thus, monitoring of drug concentrations as well as hematologic toxicity
should be applied for adjustment of etoposide doses in individual cancer patients as a means
to optimize the clinical outcome, in addition to applying a prolonged mode of etoposide
administration.
8.2.2 Fluorouracil (5-FU)
Fluorouracil is the agent of choice for treatment of colorectal cancer. Despite numerous
trials, the issue of schedule-dependency of 5-FU treatment remains controversial.65 Bolus
injection of 5-FU was shown to produce higher response rates and the same extent of toxic
effects in comparison to the same dose administered as short-term infusion (over 10-20
min).66,67 On the other hand, since 5-FU is a cell-cycle-specific antimetabolite agent,
prolonged exposure to this drug should result in 5-FU uptake by more tumor cells. Indeed, 48-
21
hr continuous infusion of 5-FU provided superior antimetabolic effect compared with bolus
administration in patients with gastric cancer as evidenced by higher extent of thymidylate
synthase (TS) inhibition in cancer cells.68 Although prolonged continuous infusion regimens
of 5-FU (over 24 hrs or more) were found to increase the response rate in comparison to bolus
injections, it did not improve the overall survival rate.69 This clinical outcome may be related
to difference in toxicity pattern produced by the different administration regimens.
In some patients tumor resistance evolves following bolus administration of 5-FU. In
this case continuous infusion of 5-FU may be applied to overcome the drug resistance.70
Administration of bolus injections and continuous infusion concomitantly or in alternating
order may serve as alternative strategy to improve the patient response.71
8.3 Optimization of anticancer treatment
Current treatment protocols of anticancer drugs do not provide optimal clinical
outcome in the terms of the response and the patient survival. In order to optimize the clinical
outcome, additional preclinical and clinical studies are needed to clarify the relationship
between the pharmacokinetic parameters and the therapeutic and toxic effects for individual
anticancer drugs. From the currently available data it seems that for cell cycle-non-specific
agents the magnitude of therapeutic drug effects is not related to the drug input rate. However,
the magnitude of adverse effects for such drugs may be significantly reduced by applying
prolonged modes of administration. For cell cycle-specific agents, prolonged mode of drug
administration should be applied to keep the drug concentrations within a certain
concentration range. This is because decrease in therapeutic effect occurs at lower
concentrations, while higher concentrations are associated with elevated magnitude of toxic
drug effects.
In addition to optimization of administration mode, profound pharmacokinetic and
pharmacodynamic variability of anticancer drugs requires application of individualized
treatment regimens for different cancer patients. Monitoring of plasma drug concentrations
may be applied to overcome the pharmacokinetic variability and to reach the target drug
exposure. However, this approach does not ensure that desired magnitude of drug effects is
attained. Monitoring of specific pharmacodynamic markers of tumor response or of toxic
effects has therefore a greater potential for reduction of inter-patient variability and for
optimization of dosing of anticancer agents.
9. Hormones: Pulsatile vs. continuous mode of administration
22
The input function of hormonal drugs is known to have a major impact on the
magnitude of therapeutic response. This phenomenon is related to physiological processes of
secretion and regulation of hormone levels in the body. Many hormones are secreted in
pulses, including insulin72,73 somatostatin, C-peptide, growth hormone (GH), PTH and
luteinizing hormone (LH). When the delivery system mimics the natural secretory pattern of
the hormone, it provides optimal hormone replacement therapy. On the other hand, the
continuous administration of large doses may suppress natural hormone secretion by
activating the feedback mechanisms in the body. Mazar has clearly described the effect of the
input function on the outcome of somatostatin derivative and for gonadotropin-releasing
hormone (GnRH).74 For somatostatin derivatives, optimal suppression of GH secretion in the
treatment of acromegaly, was obtained following a constant input rate. Similarly, if GnRH is
given continuously, gonadotropin secretion is suppressed through the mechanism of down-
regulation, which is used clinically in the treatment of prostate, endometrial and breast
cancer.75,76 On the other hand, pulsatile delivery of GnRH provides optimal response in
stimulating pituitary gonadotropin secretion. This particular response occurs because the
wave contour is a specific factor in the pharmacodynamic effects of GnRH on pituitary
gonadotropin and the steepness of the rising edge of the GnRH wave contour is a specific
determinant of pituitary LH secretion.77 In a like manner, continuous administration of
insulin down-regulates the numbers of insulin receptors, a phenomenon that can be minimized
by pulsatile insulin secretion.78
10. Anti-ulcer drugs
Current anti-ulcer treatment involves eradication the H. pylori infection by applying
antibiotic drugs, and concomitant suppression of acid secretion with H2-receptor antagonists,
or proton pump inhibitors (PPI). Since pharmacodynamic properties of the antibiotic drugs
were already discussed in the previous parts of this review, this chapter will concentrate on
the pharmacodynamic aspects of the antisecretory treatment.
The pathogenesis of acid peptic disorders, including gastric ulcers, duodenal ulcers, and
gastroesophageal reflux disease, involves an imbalance between acid secretion and gastric
mucosal defenses. The patterns of basal acid secretion in ulcer patients are similar to healthy
individuals (with the exception that ulcer patients secrete about 30% more acid) and follow a
circadian rhythm, with maximum acid secretion occuring during the early evening hours.79
The acid secretion activity is subject to high inter- and intra-patient variability; day-to-day
23
variation in the same individual can vary by more than 50%, obscuring the patient response to
anti-ulcer agent and distorting the relationship between plasma concentrations and
pharmacological response.80
It was generally accepted that ulcer healing is directly correlated to the degree of acid
suppression, and that a sustained reduction of gastrointestinal acidity (pH above 3) should be
achieved for optimal treatment results.81 Thus, the main pharmacologic approach of ulcer
healing involves decreasing of acid secretion by parietal cells using either histamine H2-
receptor antagonists, or proton pump inhibitors (PPI).
10.1 H2-receptor antagonists
H2-receptor antagonists were the most commonly prescribed agents for treatment of
peptic ulcer treatment, the main agents being cimetidine, ranitidine, and famotidine. These
drugs inhibit histamine-mediated gastric acid secretion and, thereby, produce incomplete
inhibition of acid secretion in response to meals because acid-secreting parietal cells continue
to receive stimulation via cholinergic and gastrin-mediated pathways.82 H2-receptor
antagonists may be administered via oral or intravenous routes. The duration of individual
drugs antisecretory action ranges from 6 to 12 hours.83
Repetitive dosing of H2-receptor antagonists results in rapid development of tolerance
(within several hours or days), reducing the drugs acid inhibitory effect.84 The apparent loss
of ranitidine efficacy was shown to occur within 12 hours in patients with gastric or duodenal
ulcers (see Figure 11).85 This phenomenon is thought to be mediated by the feedback
mechanisms elevating acid secretion by gastrin-mediated or alternate pathways, up-regulation
of H2-receptors, or decrease in proton pump turnover.86,87 Adverse effects are uncommon
with the H2-receptor antagonists and are generally mild.
10.1.1 Continuous vs. intermittent administration
Continuous infusions of H2-receptor antagonists were shown to maintain elevated
gastric pH for a significantly longer period of time than bolus regimens in ulcer patients,
critically ill patients, and in healthy volunteers.88-90 The gastric pH control could be achieved
at equal or lower total doses with continuous infusion.91 This apparent dose-sparing effect of
continuous mode of administration may be explained by relatively low ECmax (i.e., the
concentrations of H2-receptor antagonists that are needed to attain the maximal antisecretory
effect). Serum concentrations following bolus drug administration exceed this concentration
for a shorter period of the dosing interval than following continuous mode of administration.2
24
Additional explanation relates to the different degree of activation of tolerance-related
feedback mechanisms by bolus as opposed to continuous mode of administration. Continuous
exposure to lower doses of H2-receptor antagonists may provoke less feedback activation and
improved control of gastric acid secretion.
10.1.2 Circadian dependency
The dosing schedules of H2-receptor antagonists were considerably changed over time.
Long-term acid suppression was considered obligatory for ulcer healing, and the initial
approach applied multiple doses of H2-antagonists to reduce acid secretion for most periods of
the circadian cycle. Following this, a single daily night regimen of H2-receptor antagonists
was shown to produce better control of gastric pH compared to once-a-day morning
administration.92,93 This is because the intragastric contents are buffered by food during the
day, leading to lower apparent antisecretory effect following morning drug administration.
Inhibition of nocturnal acid secretion was considered of primary importance for ulcer healing,
and single bedtime dose had become the preferred regimen worldwide.
However, results of several clinical trials produced equivalent clinical outcome in terms
of ulcer healing of morning and bedtime doses of H2-antagonists, despite different control of
nocturnal acidity.94,95 Thus, nocturnal gastric acidity suppression is important but not
essential to promote duodenal ulcer healing. Currently, peaks of increased acidity are
considered the main factor hampering ulcer healing process, with no particular relevance to
which time of the circadian cycle during such peaks occur. Thus, efficient ulcer treatment
should prevent appearance of such peaks by implying sustained inhibition of parietal cell
activity.96
10.2 Acid (proton) pump inhibitors
The proton pump inhibitors (PPI) that were used in clinical settings include
omeprazole, lansoprazole and pantoprazole. Under strongly acidic conditions that exist in the
secretory canaliculi in the parietal cell, these drugs are converted to the active species
(sulphenamides) that irreversibly bind to the gastric proton pump (H+/K+-ATPase),
inactivating the proton transport. Thus, despite the short plasma half-life of 0.7-1.3 hours, this
covalent binding causes a prolonged duration of antisecretory effect, enabling a relatively
infrequent administration schedule.
Both oral and intravenous routes of administration of PPI were used in clinical practice.
The antisecretory effect is related to amount of the drug in the systemic circulation, and is
25
independent of the route of administration.80,97 Adverse effects occurred infrequently with
PPI agents and most commonly comprised transient gastrointestinal symptoms.
10.2.1 Administration schedule
Exposure to the relatively high doses of the drug may produce sufficient amounts of
active metabolite, which can inhibit acid secretion of actively functioning parietal cells.
However, the brief serum half-life of active metabolite may not last enough to affect other
populations of parietal cells that may be inactive at the time of administration. As a result,
populations of parietal cells that were not actively secreting acid during the time that the
active metabolite was in the serum become active afterwards and produce boots of low gastric
pH.98 Thus, the larger bolus dose provides small additional effect, and the degree of acid
inhibition increases gradually during the first days of once daily dosing because of an increase
in the number of H+/K+-ATPase enzymes inhibited (see Figure 12).80
In contrast to H2-receptor antagonists, continuous administration of PPI drugs does not
result in development of tolerance to the antisecretory effect (see Figure 11). Based on in vitro
studies, it was expected that continuous delivery of PPI drugs would inhibit more populations
of parietal cells and produce enhanced control of intragastric pH in comparison to bolus
doses.99 Intravenous administration of lansoprazole as bolus injection or infusion to healthy
volunteers was reported, however, to produce the same extent of antisecretory action.100,101
Nevertheless, these trials applied short-term (24-hour) intragastric pH monitoring and did not
necessarily represent the clinical outcomes in prolonged treatment of ulcer patients.
The higher efficiency of fractional administration of PPI drugs was confirmed in a
recent experiment when divided dosing of omeprazole provided superior gastric acid
suppression compared to once daily regimen in healthy volunteers.98 Additional studies
compared effectiveness of daily omeprazole administration with every other day or twice a
week schedules, with slightly improved clinical outcomes following once daily
administration.102-104
10.2.2 Circadian dependency
PPI drugs produce lower effects during the night than in daytime, independently of
administration time. Possible explanation to this phenomenon is that more proton pumps in
the parietal cells are activated by the repeated meal stimuli during the daytime, and become
prone to covalent binding of active metabolites, making the same dose of PPI drugs more
effective.103 Another contributing factor may be circadian dependency of the oral
26
bioavailability of the drug that yield higher plasma concentrations following morning
dosing.105,106
10.3 Optimization of anti-ulcer treatment
The concepts concerning role of overall amount of acid and relative importance of
acidity during different time intervals in ulcer pathogenesis have overcome major changes in
recent years. Currently, strong and continuous acid inhibition is not considered obligatory for
beneficial clinical outcome. Instead, short periods of elevated acidity in response to meals or
at night seem to be important pathophysiological events, whose control is sufficient to permit
quick ulcer healing.96 It seems that a small peak-preventing reduction of gastric acidity can
ensure the same therapeutic benefit as a strong and continuous acid inhibition, producing new
insights to optimized treatment regimen with antisecretory drugs.
Major pharmacokinetic and pharmacodynamic differences exist between the two
groups of antisecretory drugs, profoundly influencing the antisecretory treatment schedule.
For instance, the considerably shorter duration of action of H2-receptor antagonists in
comparison to proton pump inhibitors necessitates shorter administration intervals or
prolonged modes of administration.82 Pharmacodynamically, the antisecretory activity of H2-
receptor antagonists is weaker than that of PPI drugs (lower Emax), and decreases following
continuous exposure to the drug due to tolerance development that further reduces the drug
efficacy.84,107
As a consequence, the difference in ulcer healing rates between proton pump inhibitors
and H2-receptor antagonists103,108,109 may be attributed to different control of peaks of
elevated gastric acidity by clinically applied regimens of these drugs. Continuous modes of
administration of antisecretory drugs may provide better control of gastric acidity and
optimize clinical outcomes. For instance, continuous administration of H2-receptor
antagonists provides sustained reduction of gastric acidity and possibly prevents activation of
feedback mechanisms of acid secretion. As for proton pump inhibitors, continuous
administration may elevate treatment efficacy by increasing the number of inhibited H+/K+-
ATPase enzymes.
11. Controlled release systems in analgesia
Controlled release opioids have become well established in the management of pain,
particularly chronic cancer related pain, but also to alleviate non-cancer painful conditions
such as severe burns, surgery-induced pain, sickle-cell crisis and arthritis. While oral CR
27
morphine has predominated in this regard, other oral CR preparations have been developed
more recently, including codeine, dihydrocodeine, oxycodone and hydromorphone. In
addition, other dosage forms such as rectal morphine and transdermal fentanyl and
buprenorphine preparations have been developed for the same indications.
According to the World Health Organization recommendations, pharmacologic
treatment with morphine is considered the standard in alleviating moderate to severe pain
associated with neoplastic diseases.110 The drug can be administered via different modes and
routes, such as rapid input via multiple i.v. (or oral) bolus administrations, or in a sustained
manner by CR tablets or continuous infusion. Tolerance, manifested clinically as an increase
in the dose required over time to maintain a pain-free state, develops to the analgesic effect of
morphine.111 Despite the prevalence of this phenomenon, there is very limited quantitative
information on the rate and extent of tolerance development in humans. In particular, clinical
information is lacking about the relationship between mode of administration and the kinetics
of tolerance development. Preclinical studies in rats revealed that tolerance to morphine
antinociception developed rapidly within 8 to 12 hr during continuous i.v. infusion.112-114 A
longer period (7-10 days) is required for tolerance development during morphine
administration as multiple s.c. or i.p. bolus doses.115,116 Using a pharmacokinetic-
pharmacodynamic model that describes the development of tolerance in rats, Ouellet and
Pollack114 found that about the same degree of tolerance is achieved whether morphine is
administered as a continuous infusion or as intermittent i.v. boluses. This is because the half-
life for tolerance onset and offset is too long to allow significant sensitization between
intermittent doses. In their experimental model they showed that increasing the interval
between doses to one day does not reduce the magnitude of tolerance development during 13
days of morphine administration. This finding is in contrast to a previous report by Ekblom et
al,117 which used a similar modeling analysis to the continuous vs. bolus modes of morphine
administration. They concluded that when administering a bolus dose of morphine, the
antinociceptive effect is less influenced by the slow tolerance development than during
constant rate infusions. They observed rebound effects after cessation of the infusion but not
after the bolus dose. The half life of the tolerance development estimated in both studies was
long, between one to 3 days, that shows that tolerance develops slowly over several days.
Thus, it is not very clear if intermittent dosing reduces the degree of tolerance development,
and further pharmacokinetic/pharmacodynamic investigations are needed.
While the rationale for pursuing opioid pharmacokinetic/pharmacodynamic studies is
compelling, the complicating factors that hinder these investigations, especially in the clinical
setting, should be appreciated.118 These include: potential biases within analgesic studies,
28
that require double blind design; incorporation of the pharmacodynamics of the placebo
effect, that is known to be an inherent factor in the response to active treatments; opioid
receptors are located outside of the plasma compartment (the site of sampling), and different
opioid effects are likely to be mediated by receptors in different pharmacokinetic
compartments; metabolite activity may be of clinical importance; different concentration-
effect relationship for various pain intensity and pain characters; no stationary disease state;
development of acute and chronic tolerance; subjective methods of quantitative measurements
of pharmacodynamic effects.
11.1 Opioid analgesics
11.1.1 Controlled release formulations of morphine
The oral route is the preferred mode of morphine administration in cancer pain and the
majority of patients can be safely and effectively maintained by this route. The duration of
action after oral administration is short; therefore, if permanent relief of pain is required, the
drug has to be administered every 4 hr. For this reason, a sustained release formulation of
morphine could be very useful allowing a delay in the interval between the administrations,
from 6 times a day to twice a day, and even once daily.119 The efficacy of the marketed
formulation of CR morphine (MS-ContinR) has been demonstrated.120 The analgesic efficacy
of the CR formulations is not significantly different from that observed with reference
morphine syrup administered every 4 hr.
In addition to oral CR morphine formulations, many patients require an alternative
route of administration at some point in the course of their terminal illness. Common reasons
for the use of alternate route of morphine administration include severe nausea or vomiting,
dysphagia, bowel obstruction and severe confusion. Presently, the subcutaneous and rectal
routes represent the most widely used alternatives. The continuous subcutaneous infusion is
an effective procedure, but has certain disadvantages, including restriction of mobility and the
required frequent visits to the clinic for dosage adjustments and medication replenishment. An
improved approach is the CR morphine suppository formulations that demonstrates equivalent
pharmacokinetic and pharmacodynamic properties to the oral CR formulations.121
11.1.2 Other opioids CR formulations
Despite the extensive use of morphine, the occurrence of adverse effects necessitates
discontinuation in some patients. Clinicians treating cancer pain report significant variability
among patients in efficacy and side effects with available opioid analgesics. Patients who
29
have poor analgesic efficacy or safety outcomes with one opioid will frequently tolerate
another. This finding has led to the growing acceptance and clinical practice of opioid
rotation.122 The recent availability of opioid CR formulations such as oxycodone and
hydromorphone provides clinicians therapeutic options for cancer pain management.
Maddocks et al have shown that in patients with morphine-induced delirium, the substitution
of morphine with oxycodone results in significant improvement in the mental status, nausea
and vomiting.123 Recent evidence suggests that in addition to µ receptor-mediated analgesia,
oxycodone possesses intrinsic activity at the κ receptor, providing further rationale for its use
in treating patients unable to obtain an optimal analgesic or side effect profile with morphine
or hydromorphone.124
Oxycodone has been recently formulated into a 12 hr CR tablet which retains an onset
of analgesia as prompt as with conventional immediate-release oxycodone with majority of
patients reporting pain relief within 1 hr of administration and pain control throughout a 12-hr
period.125 The prompt onset of action results from the dual-release mechanism of the CR
delivery system. The rationale for this formulation is to avoid the need for concurrent
administration of an immediate release formulation that provide analgesia at the initial phase
after administration, until the CR formulation will constitute therapeutic concentration.
Another rationale that has been proposed for the biphasic opioid absorption profile is to
produce a peak-to-trough fluctuation comparable to conventional immediate release opioid.
This rationale is based on the suggestion, mentioned above, that very steady plasma opioid
concentrations may lead to tolerance development.117,126 The rapid onset of analgesic action
is also in accordance with the concept that have been proposed by Levy, that the rate of
decline of clinical analgesia after administration of various narcotic and non-narcotic
analgesics, and even placebos, is essentially the same, and the maximum degree of analgesia
and the duration of action is a function of Cmax.127 Thus, a rapid mode of administration that
provides larger Cmax values (that are not associated with significant adverse effects) could
provide a longer duration of pain relief than those obtained after a slower-absorbed dosage
form.
Pharmacodynamic evaluation of oxycodone revealed that minimal hysteresis occurred
between peak plasma oxycodone concentrations and peak pharmacodynamic effects,
indicating little or no delay in pharmacologic effect once oxycodone reached the systemic
circulation.118 In addition, it was found that a doubling of the dosage provided a doubling of
plasma oxycodone concentrations.128 These Cmax concentrations produced dose-related
differences in drug effect (measured with a 100 mm visual analog scale (VAS)), 40% and
60% respectively and remained sustained beyond 12 hr. The 20 mm difference in VAS drug
30
effect test is in the range reported with pain relief scales in relatively sensitive analgesic
studies with a doubling of opioid dosage, i.e., well beyond the linear portion of the log
concentration-response curve, where measurable changes in effect require dramatic changes
in opioid concentration at the receptor.118
A hydromorphone CR formulation that exhibited comparable analgesic efficacy to
oxycodone CR was associated with certain degree of hallucinations. There is extensive
clinical experience with the use of hydromorphone as an alternative to morphine. The
availability of CR formulations enables one to expand the use of this semi-synthetic congener
of morphine.
11.2 Nonopioid Analgesics
A key issue that should be taken into considerations in the pharmacodynamic rationale
to develop SR dosage forms for nonopioid analgesic drugs is the hypothesis (mentioned
above) that the analgesic effect depends on the peak blood concentration.129-131
Accordingly, the preferred mode of administration for these drugs would be by bolus (or
pulsatile) administration rather than a constant input at a slow rate. In many cases the data
support this theory. For instance, when the intensity of analgesic response to acetaminophen
was compared in mice following intravenous and subcutaneous injections, the analgesic effect
was greater after intravenous administration even at times when the blood levels after the
subcutaneous administration were higher.132 In addition, despite similar acetaminophen
plasma concentrations after short intravenous or continuous infusion, no significant analgesia
was detected after continuous infusion.133 Nielsen et al compared the efficacy of immediate
and slow release preparations of acetaminophen. Following administration of the SR tablets
the analgesic effect was lower and pain thresholds that were elevated 1 hr post-dose remained
relatively constant over the dosing interval.134 In another work, the same group found that the
acetaminophen SR preparation failed to produce any detectable analgesia.131 The hypothesis
is also supported by the data comparing the magnitude of analgesia induced by naproxen
versus naproxen sodium.135 The sodium salt that produced rapid absorption was associated
with more pronounced analgesic effect. In addition, it was found that the analgesic effect
produced by ibuprofen is stronger following soluble ibuprofen formulation that was
associated with faster absorption.136
It should be noted that beside this corroborating evidence that supports the hypothesis
of a link between the rate of decay of the analgesic effect and the peak concentration of the
analgesic compound, additional contradicting evidence exists. For instance, in a study
designed to compare the efficacy of intermittent with continuous administration of ketorolac
31
during the first 48 h after upper abdominal surgery, it was found that patients who received
the same rate of dosing of ketorolac as a continuous infusion instead of intermittent doses
showed a significant morphine sparing effect.137 Thus, more work is needed to further assess
the above mentioned hypothesis, which is a cornerstone for rationale development of
analgesic dosage for.
Another pharmacodynamic parameter that is relevant to optimizing drug formulation is
the ceiling effect detected for some of the nonopioid drugs. For instance, despite the linear
kinetics in serum drug concentrations following administration of ibuprofen 400 mg versus
800 mg, there were no differences in drug efficacy.
11.2.1 The anti-inflammatory activity of NSAIDs
11.2.1.1 Pharmacodynamic Rationale for Sustained Release formulations of NSAID anti-
inflammatory drugs
In contrast to the pharmacodynamic characteristics of the analgesic effect of NSAIDs,
superior suppression of platelet aggregation was attained following administration of a SR
preparation than following a single dose of rapid-release product.138 Similarly, it has been
shown that low concentrations of ibuprofen are required to maintain antiaggregatory activity,
which provide the rationale for a SR preparation of NSAIDs for this therapeutic goal.
11.2.1.2 Regional delivery to the site of anti-inflammatory action
The pharmacodynamic aspects of regional delivery of NSAIDs were assessed by
Martin et al in a preclinical investigation.139 They showed that direct administration of S-(+)-
ibuprofen into the site of inflammation (air pouch) produced the same concentration (at the
site of inflammation) effect relationship as intravenous administration of the drug. On the
other hand, an advantage following systemic rather than regional administration was revealed
for piroxicam, based on concentration-response analysis, indicating a major systemic anti-
inflammatory component for piroxicam but not for S-(+)-ibuprofen. These outcomes also
suggest that continuous administration of S-(+)-ibuprofen given either intravenously or via
the air-pouch, provided improved dose-response relationship in comparison to bolus
administration. This is probably because the initial exposure to high concentrations following
the bolus administration is less important than continuous exposure of the inflamed site to the
drug.
11.2.1.3 Differentiating between the effect of NSAIDs on cyclooxygenase isoforms
32
Cyclooxygenase (COX)-1 inhibition by NSAIDs is associated with gastrointestinal and
renal toxicity, while COX-2 inhibition has beneficial anti-inflammatory, analgesic and
antipyretic effects. The degree of selectivity of a given NSAID on the two distinct isoforms
COX-1 and COX-2 provide a convincing rationale for differentiating NSAIDs according to
their benefit/risk ratio. The concentration-response relationships established for the inhibition
of human COX-1 and COX-2 for meloxicam and naproxen was described recently by
Fenner.140 It was found that meloxicam inhibits COX-2 in human whole blood at
concentrations that are at least 10 times lower than those required to inhibit COX-1. In
contrast, the concentration-response curves for the inhibition of COX isoforms by naproxen
are close, suggesting approximately equipotent inhibition of COX-1 and COX-2. It is
expected that reduced fluctuations in blood concentrations due to utilization of SR
formulation for these drugs will produce higher degree of selectivity and less adverse effects
that result from the inhibition of COX-1. It could be important in view of the large inter-
subject variability in both pharmacokinetics and pharmacodynamics. Selective inhibition of
COX-2 may be achieved also applying selective COX-2 inhibitors (celecoxib and rofecoxib)
that have been marketed recently.
12. Direct administration of antiarrhythmia drugs to the heart
Conventional antiarrhythmia therapy with oral or intravenous administration is often
ineffective or results in toxic drug effects because of narrow therapeutic indices of most of
these agents. Due to the regional nature of cardiac disease it has been suggested to administer
antiarrhythmia drugs directly to the heart by localized cardiac delivery systems, based on
drug-polymer implants.141,142 This mode of administration may have several advantages,
including enhanced drug effects and reduced systemic drug toxicity. Since direct application
of the drug to the heart reduce the pharmacokinetic variability associated with absorption and
systemic disposition following conventional modes of administration, the efficacy and
toxicity would be more predicable.
The customary pharmacokinetic modeling approach cannot be used in this case, since
the heart cannot be grouped in the central compartment as drug delivered epicardially
accumulate into the heart muscle and produces a ‘depot’, from which the drug will equilibrate
slowly with various body compartments.
CR epicardial administration was tested preclinically with several drugs including
lidocaine, procainamide, verapamil and d-sotalol and proved to be safe and effective.141 For
instance, it was shown that when sotalol (a non-selective beta-blocker used for the treatment
33
of supraventricular and ventricular arrhythmias) was given by epicardial implants,
comparable myocardial concentrations of the drug were found in comparison to intravenous
administration but the total intravenous dose had to be considerably larger.142 Similarly, the
CR epicardial sotalol preparations produced electrophysiologic effects comparable to those
noted with intravenous administration at a significantly lower dose. This CR epicardial drug
delivery approach enables simple and direct ‘targeting’ of the drug to its site of action.
Thereby, it widens the therapeutic window of the drug by considerably increasing the margins
between therapeutic concentrations ‘seen’ by the target tissue and the systemic concentrations
that are associated with toxicity.
13. The antihypertensive effect of calcium antagonist drugs
13.1 The impact of rate of nifedipine administration on magnitude of
effect.
Nifedipine can be regarded as a classic example that illustrates the role of input rate on the
magnitude of effect. This calcium channel blocker has been used for several years in the
treatment of angina pectoris and hypertension. The drug was originally marketed in an
immediate release (IR) capsule formulation and later on in a sustained release tablet
formulation that had comparable bioavailability (50%). However, while the capsule produces
rapid and relatively high peak concentrations, the SR tablet gives a flat plasma concentration
profile. It was found that the increase in heart rate (side effect) was far less with the SR tablets
than with the IR capsules, whereas with both preparations a slight blood pressure lowering
effect was achieved in the normotensive subjects that were examined.143 This finding led to
the realization that the rate-of-increase in nifedipine plasma concentration (rather than the
absolute concentration) is a determining factor for the drug’s hemodynamic effects. Clear
evidence for this explanation was obtained in a study in which nifedipine was given by two
i.v. regimens designed to produce the same steady state concentration by a rapid vs. gradual
infusion rate. No increase in heart rate occurred with the slow regimen, whereas a substantial
and long lasting increase was seen with the rapid regimen.144 On the other hand, a gradual
decrease in blood pressure was observed following the slow input while blood pressure was
minimally affected. This outcome clarifies that the concentration-effect relationship of the
blood pressure lowering effect of nifedipine is shifted to the left and is steeper following a
slow input than with a rapid input rate as obtained following the administration of an IR
formulation. It has been proposed that following slow input, the activation of the
compensatory responses produced by high levels of endogenous agents such as
34
catecholamines is limited.145 Therefore, the tolerability of a SR formulation is likely to be
enhanced. There is evidence that the rate of input of nisoldipine plays a major role in its
hemodynamic activity profile,146 and it seems likely to be true for some other calcium
antagonists as well.147 These findings should not be regarded as surprising and should rather
be expected for vasodilator drugs.144,146
With a rapid decrease in peripheral vascular resistance, baroreflex activation, central
sympathetic activation and parasympathetic withdrawal serve to maintain blood pressure and
perfusion of vital organs. Heart rate and cardiac contractility increase, resulting in increased
cardiac output, and increased circulating catecholamines augment vascular resistance, that
blunts the direct drug effect. In contrast, slow drug input and gradual decrease in vascular
resistance limit this reflex activation and the direct drug effect can be more reliably observed.
13.2 Sustained release formulations as second generation of calcium
antagonists.
In order to minimize the disadvantages associated with rapid administration, and to
produce a constant plasma concentration for longer time intervals SR, extended release (ER)
and gastrointestinal therapeutic system (GITS) formulations were developed for various early
calcium antagonist medications including: nifedipine SR/GITS, nicardipine SR, verapamil
SR, and diltiazem SR, which forms the first subclass of the second generation of calcium
antagonists.148 The other subclasses comprises new dihydropyridines such as nisoldipine,
nitrenidipine, manidipine and others which posses improved pharmacodynamic and/or
pharmacokinetic properties including increased vascular selectivity.
A specific formulation developed to allow once-daily dosing of these drugs is a core
coated product, which claims equivalent efficacy to other SR formulations such as the GITS,
although the Food and Drug Administration does not consider the products to be
bioequivalent.149 The coat-core (CC) tablet consists of an external coat of slow release
nifedipine (or nisoldipine) and an internal core of rapid-release drug. The hemodynamic
effects of the long acting CC nisoldipine formulation appear to be similar to those of the
immediate release formulation, although differently timed.150
The availability of two different SR formulations of verapamil allowed some
interesting but inconclusive observations about the pharmacodynamics of the drug. Drug
pellets or beads have a much greater surface area than either tablets or caplet, which results in
faster drug release from the pellet formulation yielding a higher and earlier peak blood level,
with up to 40% increase in total bioavailability.151 However, no strong correlation exists
between blood levels and blood pressure response, at therapeutic concentrations. The data
35
suggests that once a ‘threshold level’ is reached with, verapamil higher doses and presumably
higher concentrations do not necessarily result in greater therapeutic response.152 This has
promoted the introduction of a 180-mg caplet that may represent such a ‘threshold’ dose since
its antihypertensive efficacy is similar to that of 240-mg verapamil.
13.3 The third generation calcium antagonists
The development of new molecules, including amlodipine and lacidipine, that can be
termed third generation calcium antagonists, has overcome most of the problems encountered
with the first and second generation products. Their unique characteristics are their interaction
with specific high affinity binding sites in the calcium channel complex and by the inherently
long duration of action. The lack of a clinically relevant increase in cardiac or peripheral
sympathetic activity, induced by an abrupt blood pressure reduction, is now recognized as
perhaps the most important feature of a drug of this class. However, it should be underlined
that this lack of autonomic activation does not abolish the minor vasodilator adverse events
such as flushing, headache and ankle edema that are still observed with these agents.153 The
inherently long half life (40 – 50 hr for amlodipine), and the high degree of lipophilicity,
allow their penetration deep into the lipid layer of the vascular cell membrane where the drug
is stored and slowly diffuses into a reservoir in the lipid bilayer where calcium channels are
situated.154 Therefore, it can be concluded that for these drugs no special SR formulations are
required.
14. Diuretics
14.1 General pharmacodynamic features
Diuretic drugs are commonly used for the treatment of heart failure or in hepatic, renal
or pulmonary disease when salt or water retention has resulted in edema or ascites. Several
groups of diuretic drugs are used clinically. Loop diuretics, especially furosemide, are the
most frequently prescribed and their clinical pharmacology is better understood.
The main therapeutic effects of diuretic drugs are water excretion (diuresis) and
natriuresis that are strongly interrelated. An apparent delay exists between the time of drug
administration and onset of diuretic effect. This delay may be partially attributed to
penetration of the drug to the site of action in the nephron in order to exert its therapeutic
activity. As a result, the magnitude of response is much better correlated to urine
concentration of diuretic drugs and not to the blood concentration and the pharmacodynamic
profile of diuretic drugs may be described applying a sigmoidal relationship between the
36
concentration of the diuretic in the urine and the extent of response.155,156 Since diuretic
drugs are characterized by indirect mechanism of action, their pharmacodynamics should be
more appropriately described applying indirect-response models. Recently such physiologic
indirect-response model was successfully applied to describe furosemide pharmacodynamics,
including development of tolerance to the diuretic effect following multiple dosing of the
drug.157
It was observed that the efficiency of the diuretic drug (i.e. ratio of diuretic
effect/systemic exposure) is not constant and varies profoundly with drug concentration and
time. Slow administration significantly increases the total diuretic effect per amount of drug
recovered in urine, and the cumulative diuretic effect may be highly influenced by the drug’s
administration profile.158 The extent of diuretic action is also subject to gender and age-
related inter-patient variability that may be attributed to alterations in drug metabolism,
disposition, or intrinsic diuretic responsiveness at the site of action.159,160 Diuretic efficiency
depends on additional, intra-patient factors, including development of tolerance and resistance
to drug effects. Thus, the extent of diuretic effect in specific patient is influenced by the mode
of drug administration.
14.2 Tolerance and resistance
There are two forms of diuretic tolerance: short-term and long-term. Short-term
tolerance refers to a decrease in the response to a diuretic drug following repetitive
administration. The exact mechanism by which short-term tolerance occurs is possibly related
to the activation of rapid homeostatic responses. Time course of tolerance development is
influenced by drug input rate, with slow continuous input producing less activation of
homeostatic mechanisms and elevating the overall diuretic and natriuretic effects.161 Fluid
and electrolyte replacement may prevent development of acute tolerance,162 and the results of
clinical trials applying different experimental protocols can’t be readily compared.163,164
The long-term administration of a loop diuretic leads to hypertrophy of distal nephron
segments due to unknown mechanisms. Consequently, sodium that is accumulated in the
urine in the proximal parts of nephron is reabsorbed at distal sites, leading to reduced drug
effects.165 This long-term tolerance to the loop diuretic may be partially prevented and
ameliorated by thiazide diuretic action on the distal parts of nephron. Thus, the combination
of a thiazide and a loop diuretic produces synergistic response and enhances the overall
diuretic efficiency.166
Certain clinical conditions may decrease the concentrations of the drug at the site of
action or sensitivity to the drug, producing so-called diuretic resistance. For instance, renal
37
insufficiency may decrease the delivery of the drug to the nephron and produce a
pharmacokinetic-related resistance to diuretics.167 Hepatic cirrhosis, on the other hand,
diminishes the diuretic response due to unknown pharmacodynamic mechanism, with no
effect on the amounts of diuretic drug that reach the site of action. Several other clinical
conditions (e.g., congestive heart failure and nephrotic syndrome) produce diuretic resistance
due to both pharmacokinetic and pharmacodynamic alterations.168
Several therapeutic strategies may be applied to overcome the tolerance and/or
resistance to the diuretic effect in specific clinical conditions. For loop diuretic drugs the main
strategies include changing the mode of administration or coadministration with thiazides.169
14.3 Loop diuretics
The clinically important pharmacokinetic features of loop diuretics are bioavailability
and half-life. On average, oral bioavailability of furosemide is 50 percent, but it ranges from
10 to 100 percent due to high inter- and intra-patient variability in drug absorption.170 This
wide range makes it difficult to predict how much furosemide will be absorbed in an
individual patient, and dose escalation must be applied before the drug is considered to be
ineffective. In contrast, absorption of bumetanide and torsemide is nearly complete, ranging
from 80 to 100 percent.
Loop diuretics are characterized by relatively short plasma half-lives ranging from one
hour for bumetanide to 3-4 hours for torsemide demanding frequent administration. When
short-acting diuretic preparations are applied (i.e., IV bolus or immediate release oral dosage
forms), a rapid and vigorous diuretic effect is produced for a period of up to several hours.
This rapid and excessive diuresis may cause side effects related to fluctuations in
intravascular volume and electrolyte imbalance. In addition, if the administration interval is
relatively large, the effect of a loop diuretic dissipates before the next dose is given. During
this time, the nephron can reabsorb sodium, resulting in so-called rebound sodium retention,
which may be sufficient to significantly diminish the prior natriuresis.157,171 Thus,
continuous exposure of nephron to the diuretic drug may attain higher diuretic effect with
lower risk of adverse effects.
14.3.1 Continuous intravenous infusion
In order to overcome the pharmacokinetic limitations and to prevent the development
of tolerance and resistance, a continuous intravenous infusion of loop diuretics can be applied.
Figure 13 shows that a 4 h infusion of azosemide produced higher diuretic effects in
38
comparison to IV bolus mode of administration of the same dose in rabbits.172
The superiority and better tolerability of IV infusion was confirmed in clinical studies
in patients with congestive heart failure and chronic renal insufficiency. Rudy et al gave the
same dose of bumetanide as two bolus doses separated by 6 hours or as 12-hour continuous
infusion to the patients with chronic renal insufficiency.173 The continuous infusion resulted
in significantly greater natriuretic effect (infusion, 236 ± 77 mmol, bolus, 188 ± 50 mmol, p =
0.01). The efficiency of diuretic effect for bolus and infusion modes of administration were
0.25 and 0.33 mmol/µg, respectively.
Additional advantage of continuous infusion of loop diuretics is the possibility of
gradual increase of infusion rate and accurate titration of the diuretic effect. Currently,
continuous IV infusion is widely used in clinical settings in severely ill patients, or in patients
refractory to conventional doses of loop diuretics.174 However, this mode of administration
can’t be applied in outpatient settings.
14.3.2 Sustained release formulations
The pharmacodynamic rationale of sustained input of the loop diuretics was applied for
development of sustained release (SR) dosage forms. Despite the lower bioavailability of SR
dosage forms due to limited absorption of furosemide in the distal parts of the gastrointestinal
tract, comparable diuretic effect was produced for the immediate release and SR dosage forms
of furosemide in healthy volunteers.175,176 This outcome is due to greater diuretic efficiency
for lower furosemide concentrations at the site of action (and consequently for lower drug
excretion rates), as shown in Figure 14. Thus, SR dosage forms produce prolonged exposure
of nephron to low furosemide concentrations that are associated with enhanced diuretic
efficacy.
The maximal extent of furosemide absorption is obtained in the stomach and upper
small intestine. Therefore, it was suggested that gastroretentive dosage forms of furosemide
are needed in order overcome the pharmacokinetic limitations of the drug absorption from SR
formulations.177 Several approaches to produce gastroretentive formulations of furosemide
were tested in animals178 and in human subjects179 producing encouraging results in terms of
enhanced efficiency, and reduced inter- and intra-patient variability of drug absorption.
However, despite the established pharmacokinetic and pharmacodynamic rationale,
gastroretentive dosage forms of diuretic drugs currently are not available in clinical settings.
39
14.4 Pharmacodynamic advantage of prolonged administration of
diuretic drugs
The pharmacodynamic profile of loop diuretics was extensively studied in animals and
in human patients. It was shown that prolonged continuous exposure to low drug
concentrations produces enhanced diuretic effects and is associated with reduced incidence of
adverse reactions.
Generally, prolonged kinetics of diuretic action may be achieved by several means.
One possibility is to use the drugs with relatively long pharmacokinetic half-life. However,
such drugs are not available clinically, and with currently used loop diuretics prolonged
effects may be achieved using continuous modes of administration. Continuous intravenous
infusion is commonly applied in intensive care settings, and sustained release dosage forms
may be used for peroral administration in outpatient settings.
Additional diuretic drugs may be preferably given by continuous modes of
administration. An example would be urodilatin, a polypeptide that is synthesized by the
kidney. Prolonged infusion of urodilatin lowers preload and increases diuresis and natriuresis
without neurohumoral activation or adverse side effects, and may be used as a powerful
diuretic agent in patients with congestive heart failure.180,181
15. Anti-hyperlipidemic drugs
Hypercholesterolemia plays a crucial role in the development of atherosclerotic
diseases in general and coronary heart disease in particular. The risk of progression of the
atherosclerotic process to coronary heart disease increases progressively with increasing
levels of total serum cholesterol or low-density lipoprotein (LDL) cholesterol at both the
individual and the population level. On the other hand, high plasma concentrations of high-
density lipoproteins (HDL) are associated with a reduced risk of coronary heart disease.
Drug therapy for hyperlipoproteinemia is initiated when other means including diet,
weight control, exercise and physical fitness program fail to achieve adequate results. The
drugs that are clinically used for the treatment of hyperlipoproteinemia can be divided into
two groups: compounds that lower triglyceride and cholesterol blood levels (i.e., nicotinic
acid (niacin), fibric acid derivatives), and compounds that mainly lower cholesterol levels
(anion exchange resins and hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors).
15.1 Niacin
Niacin is one of the oldest hypolipidemic drugs available, and has been in clinical use
40
for over 40 years. It is used to reduce cholesterol and triglyceride levels and, in particular, to
elevate HDL cholesterol levels. Although the drug can be regarded as relatively safe, niacin
therapy may be associated with certain adverse , some of which are directly related to the
mode of administration. Significant number of patients refrain from using this inexpensive
medication due to an intense cutaneous flush and pruritus that involve the face and the upper
part of the body. This flushing phenomenon is associated with the rapid onset of peak drug
concentration in the systemic blood circulation following oral administration of the immediate
release preparation. Continuous administration of the drug by means of SR formulations
produces a much slower rise in blood concentration and thereby reduces the flushing
phenomenon.182 On the other hand, SR formulations are far from being a simple solution
since this mode of administration produces constant exposure of the liver to relatively high
concentrations of the drug which have been reported to cause hepatotoxicity.182 However,
this severe adverse effect tends to be dose-dependent.183
The effect of mode of administration of low dose niacin on the magnitude of its
hypolipidemic effect was recently investigated in experimentally-induced hyperlipidemic
rats.182 It was found that continuous duodenal infusion, as well as SR tablets produced a
significantly larger magnitude of lipid lowering activity (reduction of both total cholesterol
and triglyceride levels) than bolus administration of the same doses. In addition, comparison
between the magnitude of lipid-lowering activity of continuous administration of the drug to
the gastrointestinal tract with equal intravenous infusion of the drug (same rate and dose)
indicated that there was no direct correlation between amounts of drug in the systemic
circulation and the magnitude of hypolipidemic response. Furthermore, no apparent effect
was detected after intravenous administration of the drug whereas continuous duodenal
administration significantly affected all three lipid components measured (cholesterol,
triglycerides and HDL serum levels). Another important finding of that investigation was that
there were no differences between the lipid lowering effects of niacin at 40 or 200 mg/kg.
This indicates that there is no apparent dose-response relationship, and no clear advantage of
higher dose of niacin. This finding is in agreement with clinical data showing that low dose
niacin (500 mg per day) produced effective lipid reduction in hyperlipidemic patients.184 The
outcomes suggest that administration of low dose niacin by an oral SR formulation will
enable safe and effective niacin therapy.
15.2 Bezafibrate
Bezafibrate is a fibric acid derivative that is used clinically to reduce blood lipoprotein
levels, especially triglycerides (TG), and elevate HDL cholesterol levels.185 On the basis of
41
pharmacokinetic rationale, specifically the relatively short biologic half life of the drug (1.5 to
2 hours), SR formulations of bezafibrate were designed and have been in clinical use during
the last decade. However, only recently, the pharmacodynamic aspects of this mode of
bezafibrate administration have been investigated.186 In that study, we assessed the role of
different routes and modes of administration of the drug on its hypolipidemic activity in three
models of experimentally-induced hyperlipidemia in rats. The work examined the hypothesis
that the major sites of bezafibrate action are located pre-systemically. Thus, continuous
administration of the drug to the GI tract is expected to augment its efficacy and provides a
pharmacodynamic rationale for an oral sustained release preparation of the drug. Indeed, the
results confirmed that equivalent doses of the drug produced significantly elevated
hypolipidemic activity when given at a slow rate directly to the GI tract compared to a PO
bolus and even to a slow IV infusion. In addition, administration of bezafibrate in a slow
release matrix tablet to the hyperlipidemic rats produced the same magnitude of effect as a
continuous duodenal infusion of the drug, thus proving the pharmacodynamic rationale for
this mode of administration for this drug. These preclinical experiments revealed lack of a
direct correlation between the systemic drug concentration and magnitude of effect. Lower
systemic drug concentrations, attained following ‘targeting’ of the drug from the gut to the
liver in a sustained manner, produced larger hypolipidemic responses in comparison to higher
systemic blood concentrations, and their respective effect, that were found following direct
administration of the drug to the systemic circulation.
It was discovered that bezafibrate undergoes a reabsorption process according to the
enterohepatic cycle. This enterohepatic cycle enhances the availability of the drug to the
presystemic sites of action (even following direct administration into the systemic blood
circulation), and is an important feature in the case of a drug like bezafibrate, and other anti-
lipid drugs, with a hepatic first pass dynamic response.
15.3 HMG-CoA reductase inhibitors
The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which
converts HMG-CoA to mevalonate. The liver is the target organ for the statins, since it is the
major site of cholesterol biosynthesis, lipoprotein production and LDL catabolism. However,
cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function, and
adverse effects of these drugs may be minimized by reduced systemic exposure to drug and
the active metabolite(s), especially during long term treatment. This can be achieved either by
specific degree of liver versus tissue selectivity of the drug and/or by targeting the drug to
their hepatic sites of action by oral SR formulation that presents the drug to the liver via the
portal veins in a sustained manner. An ideal dosing scheme would produce therapeutic levels
42
of the inhibitor to the liver at a rate that results in a hepatic extraction ratio that approaches
unity, thereby minimizing the systemic HMG-CoA reductase inhibitor levels.
McClelland et al investigated the cholesterol-lowering efficacy of an oral SR dosage
form of a potent HMG-CoA reductase inhibitor (water-soluble tromethamine salt of the 3-
hydroxyacid form of simvastatin) in comparison to bolus dosing of the drug.187 In that study,
dogs received the drug for 28 days once daily by oral bolus administrations (dry-filled
capsules) or by daily administration of an oral SR formulation (a controlled-porosity osmotic
pump). The observed mean AUC and Cmax after osmotic pump dosing were 67% and 16%
that of the bolus, respectively, while the maximum percentage decrease in serum cholesterol
was 34±8% for the SR formulation vs. 17±6% for the bolus. Combining the twofold
improvement in efficacy with the lowered systemic drug burden leads to 3- to 12-fold
‘therapeutic’ advantage from the controlled release dosage form.
The increased anti-lipid activity, taken together with the improved safety due to
reduced systemic exposure, indicate that SR formulations for these drugs may be
advantageous.
16. Levodopa therapy in Parkinson’s disease
Levodopa is the most effective treatment for Parkinson’s disease, but its efficacy is
hampered as the disease advances by clinical response modifications, namely motor
fluctuation and dyskinesias. As a result of its rapid intestinal absorption and metabolic
elimination, plasma levodopa concentration fluctuates widely in relation to each administered
dose from IR formulations. Early in the course of illness, no clear-cut relationship between
plasma levodopa profile and antiparkinson effect can be appreciated. With the progression of
the disease a correlation between levodopa plasma concentration and clinical effect
emerges,188 and in the more advanced stages the pattern of response mirrors the rapid rise
and fall in plasma levodopa concentrations after each dose (the ‘wearing-off’ phenomenon).
At this stage, the magnitude of drug effect is very sensitive even to small changes in drug
concentrations.189 Studies on the concentration-effect relationship of levodopa at this stage of
the disease demonstrated an immediate onset of the motor response when the plasma
concentration was exceeded and the appearance of off-reactions when plasma concentration
declined below this level. Controlled release preparations of the drug should provide
prolonged plasma concentrations above the ‘therapeutic’ threshold. However, fluctuations
were reported also with CR-preparations even when elevated plasma concentrations were
maintained. Harder et al investigated whether the concentration-effect relationship of
43
levodopa is influenced by the rate of drug absorption by comparing an IR and a CR
formulation.190 They found that both preparations produced the same maximal effect;
however, the estimated EC50 of levodopa were two fold higher for the CR formulation in
comparison to IR. The duration of action was approximately 1.5 longer for the CR
formulation. The gain in the duration of the motor response, which might be provided by
sustained plasma concentrations of levodopa following CR-preparation, was offset partially
by the apparent doubling of the threshold level (EC50).
The concept that rapidly changing plasma concentrations of levodopa are responsible
for the adverse effects of long-term levodopa therapy, have led to initiation of a 5-year
multicenter study that compared the efficacy and toxicity of SR vs. IR preparations of low
dose carbidopa-levodopa.191 It was found that the incidence of motor fluctuations was lower
than expected for both groups, probably due to the low dose used in this trial. In addition,
patients receiving SR preparations fared better on the activities of daily living portion of the
Unified Parkinson’s Disease Rating Scale and on portions of the Nottingham Health Profile.
Other clinical trials also exhibited somewhat better global evaluation for the levodopa CR
formulation in comparison to IR preparation.192,193
It should be noted that the oral absorption of levodopa is limited to a narrow absorption
window at the upper part of the GI tract, where absorption via active transport mechanism
takes place. Therefore, SR formulation that do not release most of its content during the first
6-8 hr after ingestion will release the drug in the colon where it will not be absorbed. The
preferred mode of administration of this drug is by gastroretentive dosage form that will
release the drug from the stomach into the duodenum in a sustained manner. Nonetheless,
such dosage form is not clinically available. In theory the best practical method to enable
constant plasma concentration of the drug would be by continuous intravenous infusion.
However, this mode of administration is not very feasible for long term use and it frequently
causes phlebitis. In addition, due to limited water solubility of the drug, large volumes have to
be infused over a day. For these reasons a new dosage form of levodopa in water dispersion
(DuodoapR) has been developed allowing the daily dose to be infused intraduodenally by a
portable pump.194 This route and form of administration have now been in use for several
years, with promising results.195 Paalzow and Sjalander-Brynne have assessed the outcome
of this mode of administration in individual patients.10 It was found that the plasma
concentration required to obtain satisfactory mobility decreased with time which indicate that
the sensitivity to the drug was elevated with time as indicated by reduced EC50 values. Since
all the patients were already on levodopa treatment for 6 to 20 years, it seems that the
improved efficacy found should be attributed to the individual titration of drug concentrations
44
for each patient together with the fact that following duodenal infusion they were not exposed
to high drug concentration (from absorption peaks). Furthermore, the fact that the infusions
were turned off during the night gave the body time to regain sensitivity, and reduce the
impact of tolerance development to the drug.
17. Antidiabetic drugs
It is well established that chronic hyperglycemia is associated with onset and
progression of diabetic complications, namely: microvascular complications, diabetic
ketoacidosis, and hyperosmolar coma. On the other hand, excessive glucose-lowering drug
regimens may produce life-threatening hypoglycemic episodes. Therefore, optimized diabetes
treatment will preserve the plasma glucose levels within the normal range throughout a 24-h
period applying appropriate mode of drug administration. In order to achieve this, physiologic
metabolic factors should be taken into account, including postprandial elevation of blood
glucose, in addition to the pharmacokinetic and pharmacodynamic properties of the specific
anti-diabetic drug. Several groups of drugs are used for diabetes treatment, including insulin
and its analogs, sulphonylurea drugs, metformin, and others.
17.1 Insulin
Insulin and its analogs have been used for several decades for treatment of diabetes
mellitus. Generally, a higher dose of insulin is associated with higher glucose-lowering effect,
and the sigmoid Emax model may be applied to describe the dose-response relationship.196
As seen in Figure 15, a temporal delay exists between the insulin blood concentrations and
glucose-lowering effect (resulting in counter-clockwise hysteresis) due to indirect mechanism
of insulin action and sustained penetration to the peripheral sites of action. The extent of
insulin effect is subject to inter- and intra-subject variability, and depends on administration
route, glucose blood level, liver function, and factors related to insulin resistance.197 Thus, in
order to reach appropriate glucose control in the individual patient, treatment regimen should
apply insulin analogs or formulations with different duration of action, and glucose blood
testing should be performed for dose adjustment in the initiation and throughout the treatment.
17.1.1 Physiology of insulin secretion
Insulin secretion from the pancreatic β-cells is pulsatile in nature and is regulated by
several feedback mechanisms related to glucose and insulin blood levels. Two types of
45
oscillations are recognized, with rapid pulses of approximately 10 min periodicity198 being
superimposed on much slower waves (every 50-100 min).199
It is not clear if mimicking of pulsatile pattern of insulin secretion is beneficial for
clinical outcome. In some trials, pulsatile intravenous administration of insulin to diabetes
patients was found to be more efficient than continuous delivery in reducing blood glucose,
lowering glucosuria, increasing insulin sensitivity and inhibiting lipolysis.200-202 However, a
number of clinical trials produced similar metabolic effects for pulsatile and continuous
modes of insulin administration.203-205 Variable degree of mimicking of insulin secretion
pattern in the individual studies (i.e., differences in pulse intervals and amplitude) may
explain the difference in metabolic outcomes. So far, pulsatile insulin delivery is rarely
applied in clinical practice and is mainly reserved for patients who are unable to attain the
tight glucose control through conventional means.206
17.1.2 Route of administration
The most common route of insulin administration remains subcutaneous injection.
Intraperitoneal insulin administration has been claimed to offer better glycemic control and
insulin sensitivity than subcutaneous insulin by producing a more ‘physiologic’ ratio between
portal and peripheral insulin concentrations. However, it was associated with enhanced liver
inactivation of insulin, reducing the peripheral effects and producing disadvantageous effect
on serum lipids.207,208
Despite considerable efforts, oral administration of insulin is not available clinically
due to rapid destruction of insulin in the gastrointestinal tract and limited absorption to the
systemic circulation. The benefits and limitations of alternative non-invasive routes of insulin
administration, including intranasal, inhaled, r, etc., are thoroughly discussed in recent
reviews.197,209-211
17.1.3 The administration schedule
The so-called ‘conventional’ treatment regimens have been used for most diabetic
patients. Their main advantages are simplicity, safety and ease of compliance for the patients,
but they can’t achieve perfect control of blood glucose. For more strict control of the blood
glucose levels, ‘intensive’ regimens were developed, requiring multiple injections of insulin
during the day to mimic the physiologic demands of insulin that are increased following
meals.
Continuous insulin infusion may provide improved glycemic control in patients that
46
still can produce their own insulin in response to postprandial hyperglycemia. Continuous
infusion produced improved metabolic effects compared to conventional insulin therapy in
diabetes patients,212,213 and in patients with diabetic ketoacidosis.214
Nighttime glucose control is difficult to achieve because of circadian variations in the
pharmacodynamics of insulin.215,216 The early morning requirement for insulin is twice as
much as the daytime demand and is related to alterations in cortisol and growth hormone
secretion.217 Therefore, the bedtime dose of either intermediate or long-acting insulin218 or
continuous insulin infusion may be applied to improve nocturnal glycemic control.219
17.1.4 Optimization of insulin treatment
The insulin requirement and sensitivity throughout the day depends on the metabolic
condition of the diabetes patient, and the pharmacokinetic and pharmacodynamic features of
the drug formulation. Current treatment protocols apply multiple daily glucose self-tests to
adjust the insulin doses and to prevent periods of excessive or insufficient hypoglycemic
activity. Various strategies applying novel insulin analogs, changing the dose, timing and the
route of the administration, were shown to improve, but not completely optimize glycemic
control in diabetic patients.
Further optimization of insulin treatment may be achieved using glucose-controlled
feedback (closed-loop) systems. Such a system consists of glucose sensor, insulin pump, and
pump control system and may simulate the physiologic release of insulin in order to reach the
target blood glucose concentrations. Currently, closed-loop systems may provide satisfactory
control of diabetes for over a year, with the major complication being obstruction of the
infusion catheter.220 In the future, the ultimate goal of diabetes treatment may be achieved by
restoring the feedback regulation of glucose homeostasis on the cellular level by implantation
of genetically-engineered β-cells with controlled insulin-releasing activity.
17.2 Sulphonylurea drugs
Sulphonylurea derivatives are hypoglycemic drugs frequently used in the treatment of
type 2 diabetes mellitus (NIDDM). The mechanism of action of sulphonylurea drugs involves
receptor-mediated blockade of ATP-sensitive potassium channels (KATP), that stimulate
insulin release by the pancreatic β cells and the contraction of vascular smooth muscle cells.
The later effect leads to impairment of the myocardial contractile function and exacerbation
of the myocardial ischemia, but the extent of its clinical relevance is still not clear.221,222
Different sulphonylurea derivatives may differ in their selectivity to
47
pancreatic/extrapancreatic effects.223
Additional adverse effects of sulphonylurea drugs are related to excessive blood
glucose reduction, leading to life-threatening hypoglycemic episodes, especially in elderly
patients. Short acting sulphonylurea drugs are clinically safer due to lower risk and duration
of such episodes.224 Continuous exposure of pancreatic β-cells to high concentrations of
sulphonylurea drugs induces down-regulation of β-cell sensitivity and development of
tolerance (i.e., reducing the extent of insulin-releasing effect).223,225
The dose-response relationship of sulphonylurea drugs is characterized by pronounced
interindividual variability. A recent study by Rydberg et al investigated concentration-effect
relationships for both glibenclamide and its metabolites after oral and intravenous
administration to healthy volunteers.226 Profound counterclockwise hysteresis was observed
following administration of the parent drug or the metabolites as a result of indirect
mechanism of hypoglycemic action of sulphonylurea drugs. The results of the study imply
that the major metabolites of glibenclamide possess a higher hypoglycemic activity at low
concentrations than the parent drug, contributing to prolonged duration of action following
glibenclamide administration.
The pharmacokinetic characteristics of specific sulphonylurea analogues or drug
formulations may be clinically relevant, determining the time to onset of action, magnitude
and duration of the glucose-lowering effect, and timing of drug administration in relation to
food intake. Immediate release preparations of short-acting sulphonylurea drugs may totally
abolish the meal-related elevation in plasma glucose when correct timing is achieved between
the mealtimes and the drug administration. On the other hand, sustained-release formulations
and longer-acting analogs provide prolonged hypoglycemic activity, but only partially
diminish the meal-related elevation in plasma glucose. In this case rapid-acting insulin
preparations are added to the treatment schedule to further reduce the fluctuations in blood
glucose levels.
Sulphonylurea therapy should always be initiated and maintained at the lowest possible
dose. This is because the use of high doses that are associated with elevated incidence of
cardiovascular and hypoglycemic adverse effects leads to diminished efficiency of anti-
diabetic treatment. On the other hand, prolonged exposure of the β cells to high doses of
sulphonylurea drugs may reduce the extent of desired effects due to development of
pharmacodynamic tolerance.
17.3 Metformin
Metformin is a biguanide antihyperglycemic agent widely used in the management of
48
type 2 diabetes mellitus (NIDDM). Metformin lacks a direct insulin-releasing effect. In the
diabetic state its main actions include antihyperglycemic, weight-stabilizing, lipid lowering,
and insulin-sensitizing effects. Unlike sulphonylurea drugs, metformin does not lower the
blood glucose below the normal levels in diabetics and, therefore, is safer in clinical use. The
mechanism of action of metformin is combined from several distinct effects in various organs
and tissues, including inhibition of gluconeogenesis in the liver, reduction of glucose
absorption, elevation of glucose metabolism in the intestine, and indirect inhibition of
lipolysis in adipose tissue.227
It seems that the multifactorial mechanism of action of metformin obscures the dose-
response relationship of the metabolic effects in individual organs and tissues and complicates
the optimization of metformin treatment. Generally, low metformin concentrations seem to
improve peripheral insulin resistance, and at higher concentrations a direct glycemia-lowering
effect occurs (mainly via inhibition of hepatic gluconeogenesis) leading to further reduction
of hyperglycemia.228
The overall metabolic effects of metformin seem to be concentration related.
Metformin concentrations were shown to be inversely correlated with serum triglycerides and
directly correlated with high density cholesterol (HDL), but not with metformin dose or
fasting plasma glucose.229 However, the same group of researchers found later that an inverse
correlation exists between metformin concentrations and plasma glucose levels. In addition, a
significant correlation was observed between mean plasma metformin concentrations and
mean plasma lactate levels.230
The overall extent of drug effects depends on the physiological and metabolic state of
the patient and the local tissue concentrations of the drug. However, the relative significance
of central and peripheral sites of metformin action to produce metabolic effects remains
unknown and seems to vary in different experimental conditions.227
We have shown that bolus administration of metformin to the small intestine provides
enhanced glucose-lowering effects in comparison to IV bolus administration of the equivalent
dose to streptozotocin-induced diabetic rats.231 This outcome is due to pharmacokinetic
differences between the two modes of administration. Following IV bolus, metformin is
extensively eliminated from the blood and concentrations rapidly drop below the therapeutic
window. Following oral or intra-intestinal administration, metformin accumulates in the
intestinal mucosa cells and is absorbed slowly to the systemic circulation.232 As a result, flip-
flop pharmacokinetic behavior is observed and therapeutic drug concentrations are kept for
prolonged period of time.
Accumulation of metformin in the intestinal mucosa produces a ‘natural’ sustained
49
release system. Due to this, similar magnitude of glucose-lowering effect is attained when
metformin is given intra-intestinally as bolus dose or continuous infusion.231 Thus, sustained
release of metformin in the gastrointestinal tract does not offer pharmacodynamic advantage
over immediate release formulations with respect to the hypoglycemic effect. However,
metformin accumulation in the intestinal mucosa apparently leads to gastrointestinal
intolerance, a very common adverse effect seen in up to 20% of patients.233 Gradual release
of metformin from CR formulations reduces the extent of accumulation and decreases the
incidence of gastrointestinal adverse effects. Results from clinical trials confirm the better
tolerability profile of CR formulations of metformin in comparison to regular dosage forms.
18. Optimal mode of organic nitrate administration
Organic nitrates are direct-acting vasodilators. They are metabolized by vascular
smooth muscle cells to form nitric oxide (NO). The NO then interacts with endogenous thiols
to form S-nitrothiol. Both NO and S-nitrothiol activates guanylate cyclase to produce cyclic
guanosine monophosphate which causes smooth muscle relaxation. The dilation of the venous
system results in a reduction of left ventricular end-systolic pressure and volume and
ultimately of oxygen consumption. Due to these activities, the organic nitrates were proved to
be effective agents in the management of acute episodes of angina pectoris and are
particularly useful in angina prophylaxis.
While the organic nitrates are extremely effective in prophylaxis, in acute therapy it
was found that continuous administration of these drugs by either oral or transdermal therapy
cause substantial attenuation of the antianginal effects. Thus, during acute therapy the organic
nitrates improve exercise tolerance for many hours, but during sustained therapy designed to
provide constant effective nitrate concentration throughout a 24-hr period there is significant
attenuation of the beneficial effects due to development of tolerance (for review see
Abrams234 and Elkayam235). Thus, steady-state nitrate levels are undesirable during
sustained therapy and therapeutic regimens must be developed to provide a low-nitrate period
during a significant portion of the 24 hr period.
These findings demonstrate clearly the necessity to consider the pharmacodynamic
properties of the drug during the development stages. Moreover, they emphasize the
important role of the mode of administration on the magnitude of response and the need to
assess the concentration-effect relationship characteristics over time. The initial development
of nitroglycerine (as well as other nitrates) SR formulations was based solely on a
pharmacokinetic approach. This approach concentrated on overcoming the short biological
50
half-life of the drug (several minutes for nitroglycerine), and maintaining steady state drug
concentrations over prolonged periods, that could be produced with various transdermal
formulations. This pharmacokinetic approach was based on the simplistic assumption that
constant blood concentration guarantees constant magnitude of response. The
pharmacodynamic information about the acute tolerance was found only after these products
were already on the market. These pharmacodynamic findings clarified the need for a drug-
free period for the vasculature to regain its reactivity toward organic nitrates. The drug free
period was found to be independent of drug formulation.
In conclusion, the ideal nitrate and formulation that can produce around-the-clock
protection against effort-induced angina is not yet available. When nitrates are used for
prophylaxis, differences in the pharmacokinetic properties of the different organic nitrates are
largely obviated by the SR pharmaceutical formulations, and there is no major
pharmacological reason to choose one nitrate over another. Several SR formulations,
including oral and transdermal products can provide objective anti-ischemic protection for
about 12 hr out of a day. The use of a drug free interval of 8-12 hr appears useful in avoiding
the development of pharmacological tolerance in some patients.236
19. Conclusions
The review furnishes insights into the important dimension of the input function of
drug administration. It draws a picture of the present available information in this area by
concentrating on relevant pharmacodynamic data that has been reported on drugs from
selected pharmacologic and therapeutic categories
This review highlights the important role of the mode of drug administration in
affecting the magnitude of response and thereby modifying the outcome of drug therapy. It
clarified the fact that in many cases the same dose of drug can produce very different
therapeutic outcome when administered by different modes of administration. It is important
to acknowledge this fact when comparing different pharmacotherapy protocols, especially
nowadays, when ‘evidence-based medicine’ (EBM) is becoming the rule in determining the
proper therapeutic protocol. This is because EBM, that is based on finding previous reports to
answer a specific clinical question, is mainly focused on the type of the drug and the dose
while paying not enough attention to the mode of drug administration. Moreover, this issue
should be emphasized for those scientists associated with performing meta-analysis of
randomized controlled clinical studies in order to determine optimized therapeutic guidelines.
In the last few years, there has been an increasing awareness of this subject and more
investigations that compare pulse dosing to sustained delivery of the drug have been reported.
51
In addition, further pharmacodynamic end points or surrogate markers that enable graded
measurement of effect are becoming available. Thus, it is foreseen that in the future,
pharmacodynamic aspects of drug delivery (that have been relatively ignored in the past) will
be incorporated together with the extensive knowledge that has been gained on the physical
aspects of drug delivery systems and the pharmacokinetic properties of drugs in order to
establish a sound rationale for optimized temporal patterns of drug therapy.
Acknowledgments:
Dr. Amnon Hoffman is affiliated with the David R. Bloom Center for Pharmacy.
52
Legends:
Figure 1: Illustration of distinct zones of concentration ranges along the sigmoid Emax
pharmacodynamic profile (from Hoffman,2 with permission).
Figure 2: Simulation of pharmacokinetic and pharmacodynamic behavior of the drug
following administration of the same total dose as IV bolus or constant infusion over 2, 4, 8 or
12 hours. The concentration vs. time profiles were based on a one compartment model, and
the effect vs. time data was produced applying sigmoid pharmacokinetic/pharmacodynamic
curves of different shape (n = 0.5, 1, or 4).
Figure 3: Simulation of area under the effect curve (AUEC) after administration of low ( ),
medium ( ), and high ( ) dose of the drug by bolus or continuous infusion modes of
administration for Models I, II, III, and IV of indirect drug response (from Gobburu and
Jusko,4 with permission).
Figure 4: Relationship between the time above the MIC and bacteriologic cure for various
beta-lactams against S. pneumoniae (O) and H. influenzae (∆) in patients with otitis media.
The solid and open symbols represent data obtained with penicillins and cephalosporins,
respectively (from Craig,28 with permission).
Figure 5: Effect of increasing the dose or changing the dosing regimen of a hypothetical drug
on peak/MIC ratio, AUC/MIC ratio, and duration of time that serum levels exceed the MIC
(from Craig and Andes, 38 with permission).
Figure 6: Relationship between the 24-hour AUC/MIC ratio of fluoroquinolones and survival
among animal models infected with a variety of gram-positive and gram-negative pathogens.
The solid and open circles represent data obtained in the thigh-infection model and in other
models, respectively (from Leggett et al, 37 with permission).
Figure 7: Inhibition of DNA precursor incorporation by doxorubicin. Human bladder tumor
histocultures were treated with doxorubicin for 2 h. Drug effect was measured as an inhibition
of the incorporation of BrdUrd. , average of all tumors; O, the most sensitive tumor; , the
most resistant tumor (from Gan et al,50 with permission).
53
Figure 8: Maximum BUN levels versus Cmax and AUC after single bolus injections ( ) and
3-h infusions ( ) of unchanged cisplatin (from Nagai and Ogata,55 with permission).
Figure 9: Relationship between AUC estimated by plasma concentration of unchanged
cisplatin greater than 0.9 µgPt/ml and maximum BUN level. O, Bolus injections; ∆, 3-h
infusion; , 2-h infusion; ∇, intermittent bolus injections (from Nagai and Ogata,55 with
permission).
Figure 10: Survival curve for patients treated with 24-hour continuous infusion and five-daily
infusions of etoposide (from Slevin et al,61 with permission).
Figure 11: Median percentage of time spent above pH thresholds of 4, 5.4, 6, and 6.8 during
the 2nd to 12th hour and the 13th to 24th hour with ranitidine or omeprazole in patients with
bleeding from either duodenal or gastric ulcer (* p < 0.003) (from Labenz et al,85 with
permission).
Figure 12: Median intragastric pH profile before and after the first and fifth daily morning
dose of omeprazole, 20 mg PO, 10 mg IV, and 40 mg IV (from Cederberg et al,80 with
permission).
Figure 13: Cumulative urine output and mean cumulative urinary excretion of sodium as
function of time following 1 min ( ) and 4 h (O) infusion of azosemide, 1 mg/kg, to rabbits
(from Park et al,172 with permission).
Figure 14: Diuretic efficiency (urine volume adjusted for basal diuresis per amount excreted
furosemide) vs. furosemide excretion rate following three 60 mg oral dosage forms during the
first 4 hr after dose ( plain tablets, Furix retard®, Lasix retard®) and from 4 to 24 h (- - -
). Arrows indicate direction of hysteresis (from Alvan et al,176 with permission).
Figure 15: Relationship of measured serum concentrations to the glucose infusion rate for
both regular and NPH insulin. Arrows indicate direction of hysteresis (from Woodworth et
al,196 with permission).
54
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