biopharmacy and pharmacokinetics

Biopharmacy and pharmacokinetics

SUMPh Nicolae Testemitanu

Drug technology department

Ciobanu Cristina, Dr., Associat professor

LECTURE Nr. 2

CONTENT

• 1. Notions of body compartment and pharmacokinetic models.

• 2. Kinetic processes. Kinetic processes of order 0 and order 1 in pharmacokinetics. Kinetics Michaelis-Menten.

• 3. Compartmental pharmacokinetic models and pharmacokinetic parameters

• 4. Factors that influence pharmacokinetic parameters.

Ciobanu Cristina, PhD - Biopharmacy

PHARMACOKINETIC MODELS:

• • MONOCOMPARTMENTAL;

• • TWO COMPARTMENT;

• • TRICOMPARTIMENTALE

Compartment - virtual (possible) volume of the organism in which MS is instantly and evenly distributed

• OPEN MONOCOMPARTMENTAL PHARMACOCINETIC MODEL DESCRIBES THE KINETICS OF PLASMATIC OR URINARY CONCENTRATION AFTER ORAL OR INTRAMUSCULAR ADMINISTRATION


MONOCOMPARTMENTAL PHARMACOKINETIC

MODEL open to administration IV


BICOMPARTMENTAL

PHARMACOKINETIC MODEL

open to administration IV


2. OPEN BICOMPARTMENTAL PHARMACOKINETIC MODEL

Central compartment (blood, extracellular fluid, liver, kidneys)

PERIPHERAL COMPARTMENT (ORGANS AND TISSUES WITH LOW IRRIGATION, MUSCLE, ADIPOS TISSUE ...)

DISPOSAL HAS PLACE IN THE CENTRAL COMPARTMENT

TRICOMPARTMENTAL

PHARMACOKINETIC MODEL

open to administration IV


Open

tricompartmental

pharmacokinetic model

central compartment and 2

peripheral compartments with

different accessibility for

medicines (pregnant)

In the "beta" phase

the concentration balance is

established in different

compartments

(Apparent distribution

balance)

Pharmacokinetic Parameters

Clearance

Volume of distribution

Half-life

Bioavailability

Plasmatic concentrationCiobanu Cristina, PhD - Biopharmacy

Volume of distribution

1.Vd ~ 3 l - the distribution takes place in the vascular fluid (water volume of the circulating plasma, about 4% of the body mass

2.Vd ~ 12 l - (17% of body mass) - extracellular distribution

3.Vd ~ 41 l - (58% of body mass) - distribution takes place in all available biological fluid

Metabolism and elimination affect the free molecules. The bound form is excluded from these processes. High values of Vd often correspond to slow purification


Volume of Distribution


- quantifies DISTRIBUTION

- relates drug concentration (Cp)to amount of drug in the body (X)

- gives information on the amount of drug distributed into the tissues

Vd = X / Cp

Dicloxacillin 0.1 L/kg

Gentamicin 0.25 L/kg

Antipyrine 0.60 L/kg

Ciprofloxacin 1.8 L/kg

Azithromycin 31 L/kg

Volume of Distribution


Half-Life

Half-life is the time it takes for the concentrationto fall to half of its previous value

Half-life is a secondary pharmacokinetic parameter and depends on clearance and volume of distribution

CL

Vdt

693.02/1 kk

t693.02ln

2/1


BIOAVAILABILITY• - "Fraction of a dose of drug that is absorbed from its site of

administration and reaches, in an unchanged form, the systemic circulation.“

When the drug is administered orally the bioavailability depends on several factors:

• Physicochemical properties of the drug and its excipients that determine its dissolution in the intestinal lumen and its absorption across the intestinal wall.

• Decomposition of the drug in the lumen.

• pH and perfusion of the small intestine.

• Surface and time available for absorption.

• Competing reactions in the lumen (for example of the drug with food).

• Hepatic first pass efect


BioavailabilityRate and Extent of Absorption


Kinetic proceses• First order elimination kinetics: a constant proportion (eg. a percentage) of

drug is eliminated per unit time

• Zero order elimination kinetics: a constant amount (eg. so many milligrams) of drug is eliminated per unit time

• First order kinetics is a concentration-dependent process (i.e. the higher the concentration, the faster the clearance), whereas zero order elimination rate is independent of concentration.

• Michaelis-Menten kinetics describes enzymatic reactions where a maximum rate of reaction is reached when drug concentration achieves 100% enzyme saturation.

• Non-linear elimination kinetics is the term which describes drig clearance by Michaelis-Menten processes, where a drug at low concentration is cleared by first-order kinetics and at high concentrations by zero order kinetics (eg. phenytoin or ethanol).


• First order elimination kinetics

• "First-order kinetics... is where a constant fraction of drug in

the body is eliminated per unit of time"

• This is a logarithmic function. All enzymes and

clearance mechanisms are working at well below their

maximum capacity, and the rate of drug elimination

is directly proportional to drug concentration.


The drug concentration halves predictably according to fixed time

intervals. When you plot this on a semi-logarithmic scale, the

relationship of concentration and time is linear.


Zero-order elimination kinetics

• In chemistry, when doubling the concentration of

reagents has no effect on the reaction rate, the increase

in rate is by a factor of 0 (i.e. 20). This is zero-order

kinetics. The relationship of concentration to

reaction rate can therefore be plotted as a boring

straight line:


• In the realm of pharmacokinetics, "reaction rate" is elimination of the drug, by

whatever clearance mechanisms (some of which might actually involve reactions).

• Generally speaking first-order kinetics can describe clearance which is driven

by diffusion; diffusion rate is directly proportional to drug concentration.

• If there is a functionally inexhaustable amount of metabolic enzymes available,

the reaction will also be first order (i.e. the more substrate you throw at the

system, the harder the system will work). However, if there is some limit on how

much enzyme activity there can be, then the system is said to be saturable, i.e. it is

possible to saturate the enzymes to a point where increases in concentration can

no longer produce increases in enzyme activity.

• This gives rise to non-linear elimination kinetics, known by the uninformatively

eponymous term "Michaelis-Menten elimination".


Michaelis-Menten elimination

kinetics Named after Leonor Michaelis and Maud Menten, this model of enzyme

kinetics describes the relationship between the concentration and the rate of enzyme-mediated reaction. In short, at low concentrations, the more substrate you give the faster the reaction rate.

At high concentrations, the rate of reaction remains the same because all the enzyme molecules are "busy", i.e. the system is saturated.

This concept can be described by the unimaginatively named Michaelis-Menten equation, which relates the rate (velocity, V) of a reaction to the concentration of the substrate (lets call it "drug").

A maximum rate of reaction is reached when drug concentration achieves 100% enzyme saturation. Beyond this concentration, clearance will be zero-order.

The maximum rate of reaction in this instance is called Vmax (i.e. maximum velocity). The concentration required to achieve 50% of this maximum reaction rate is called Km, where K presumably stands for Konzentration because everything in science was named by the Germans.


• A compartment in pharmacokinetics is an entity that can be described by a definite volumeand a concentration of a drug contained in that volume, which may be:

• 1. Central Compartment The central compartment includes blood and the highly perfusedorgans and tissues such as heart, brain, lungs, liver, and kidney. In these organs, theadministered drug usually equili‐ brates rapidly.

• 2. Peripheral Compartment(s) This compartment(s) include(s) those organs that are less well-perfused such as adipose and skeletal muscle, and therefore the administered drug willequilibrate more slowly in these organs. The duration of the drug effect at the target tissuewill often be affected by the redistribution from one compartment to another. For example, the general anesthetic drug, thiopental, which is a highly lipid-soluble agent, inducesanesthesia within seconds owing to drug rapid equilibration between blood and brain. Theduration of anesthesia is short due to drug redistribution into adipose tissue, which can act asa storage site, or drug reservoir, although thiopental is slowly metabolized.

• 3. Special Compartments Drug access to some body parts such as the cerebrospinal fluid(CSF) and central nervous system (CNS) is controlled by the structure of the CNS bloodcapillaries and the outermost layer of the neural tissue, i.e., pericapillary glial cells (the choroidplexus is an exception). Also, some drugs have relatively poor access to pericardial fluid, bronchial secretions, and fluid in the middle ear, thus making the treatment of infections inthese regions difficult. These special compartments deserve mention as a separate category.

• This model represents the simplest way to describe the process of drug distribution as well as elimination in the body.

• In this model, the body acts like a single, uniform unit in which the drug can enter or leave the body easily (i.e., the model is “open” for the drug movement).

• For IV bolus administered drugs, the entire dose enters the bloodstream directly.

• This is followed by distribution of the drug through the circulatory system to all the tissues in the body.

• Concentration of the drug in various tissue organs or the process of drug distribution in the body will occur depending on the blood flow to the tissue, the molecular weight of the drug, the drug lipophilicity, plasma protein binding, and the binding affinity of the drug toward certain tissue.

• Mostly, drugs are eliminated from the body either through the kidney and/or the liver following drug metabolism.

One-Compartment Open Model:

Intravenous Bolus Administration

• A typical rectilinear (a) orsemilogarithmic (b) plot of rateof excretion against averagetime t following theadministration of a drug as anintravenous bolus.

• Ku, first-order renal excretionrate constant;

• X0, drug at time zero;

• K, elimination rate constant.

Intravenous infusion• Initially, the rate at which drug enters the body, though constant,

is greater than the rate at which drug is eliminated; this allows the

drug to reach a certain amount and concentration in the body.

• During administration of a drug by IV infusion, the plasma drug concentration starts to increase and the rate of drug elimination will also increase since the latter is concentrationdependent. Cp keeps increasing until a steady-state condition is reached at which the rate of drug input (IV infusion rate) equals the rate of drug output (elimination rate).

• At this stage, a steady-state (CSS) is reached and the resulting plasma drug concentration is directly related to the rate of infusion and inversely related to the body clearance of the drug.

• For drug administered by IV infusion, the therapeutic activity is observed when the concen‐ tration of the drug is close to the desired plasma concentration, which is usually the required steady-state drug concentration.

• The time to reach steady-state could be determined by knowing the time to reach half the steady-state which can be derived:

Examples

• A drug belonging to the cephalosporins antibiotics has a volume

of distribution of 10 L and an elimination rate constant (k) value

of 0.2 hr– 1.

• A steady-state plasma concentration of 10 µg/mL is desired.

What is the infusion rate required to maintain this concentration.

• Solution -

• R = Css * Vd * Kel =

• 10 *(10 *1000)* 0.2 = 20 mg/hr

Multiple dosing: intravenous bolus

administration

• Some drugs, such as analgesics, hypnotics and

antiemetics, may be used effectively when

administered as a single dose. More frequently,

however, drugs are administered on a continual basis.

In addition, most drugs are administered with

sufficient frequency that measurable and, often,

pharmacologically significant concentrations of drug

remain in the body when a subsequent dose is

administered.

Extravascular administration• Unlike the process of IV administration, when a drug is introduced into the body by

extrava‐ scular route such as oral, intramuscular, subcutaneous, or transdermal administration, an absorption phase that transfers the drug from the absorption site into the systemic vascular system must take place.

• The oral route of drug administration represents the most popular of the extravascular routes.

• The plasma level time curve for drugs administered by intramuscular, subcutaneous, or transdermal showed the same profile for orally administered drugs.

• Also, it is important to mention that for the same route, different drug formulations such as oily, aqueous liquid, suspension, emulsion, semisolid, fast dissolving tablets, oral disintegrating tablets, or buccal tablets exhibit the same plasma time curve but with slight modification in the rate and extent of absorption and/or distribution phases.

• This concept is common during relative bioavailability study that involves identification of a significant difference between different pharmaceutical products administered by the same or another non-intravenous route of administration.

• The process of oral drug absorption (drug input) is mainly first-order, unless

it has been verified experimentally or through the pharmacokinetic models

that it is zero-order.

• The figure below represents the plasma-level time curve for a drug

administered by oral route; unlike the IV bolus, there is an absorption phase

and the overall rate of change in the amount of the drug in the body dDB

/dt is the function of both the rate of drug absorption and elimination.

• The maximum plasma concentration is represented as Cmax, and the time

needed to reach maximum concentration is represented as tmax.

Factors that influence pharmacokinetic

parameters

Factors

PhysiologicalAge, sex,

pregnancy

PathologicalHeat, liver,

kidney failures

Pharmacokinetics in renal disease.

• The physiologic perturbations associated with renal diseasecan have a pronounced effect on the kinetics ofelimination of drugs and their metabolites from the body. Drugs are ordinarily cleared from the body by a numberof routes, each of which can be characterized by a clearance value.

• The sum of these clearances (renal, hepatic, etc.) is thetotal or body clearance which is inversely proportional tothe steady-state plasma concentration produced by a givendrug dosage regimen.

• The quantitative contribution of each route of eliminationto the metabolic fate of a drug is proportional to theclearance value of that route relative to the body clearance. As a first approximation, the reduction in the renalclearance of a drug caused by renal disease is proportionalto the reduction in the renal clearance of creatinine.

Congestive heart failure• is associated with hypoperfusion to various organs including the

sites of drug clearance, i.e. the liver and kidneys. It also leads toorgan congestion as seen in the liver and gut.

• The main changes in drug pharmacokinetics seen in congestiveheart failure are a reduction in the volume of distribution andimpairment of clearance.

• The change in elimination half-life consequently depends onwhether both clearance and the apparent volume of distributionchange, and the extent of that change.

• Pharmacokinetic changes are not always predictable in congestiveheart failure, but it seems that the net effect of reduction in thevolume of distribution and impairment of clearance is thatplasma concentrations of drugs are usually higher in patients withcongestive heart failure than in healthy subjects.

• The liver plays a central role in the pharmacokinetics of many drugs. Liverdysfunction may not only reduce the plasma clearance of a number of drugseliminated by biotransformation and/or biliary excretion, but it can also affectplasma protein binding which in turn could influence the processes ofdistribution and elimination.

• In addition, reduced liver blood flow in patients with chronic liver disease willdecrease the systemic clearance of flow limited (high extraction) drugs andportal-systemic shunting may substantially reduce their presystemicelimination (first-pass effect) following oral administration.

• When selecting a drug and its dosage regimen for a patient with liver diseaseadditional considerations such as altered pharmacodynamics and impairedrenal excretion (hepatorenal syndrome) of drugs and metabolites should alsobe taken into account.

• Consequently, dosage reduction is necessary for many drugs administered topatients with chronic liver disease such as liver cirrhosis.

Pharmacokinetics in liver disease

Chrono-pharmacokinetics

Chronobiology – Science that studies the biological rythms •

Chrono-Pharmacokinetics – Deals with study of temporal changes in ADME- due to time of administration •

Chronokinetics – Time dependent changes in ADME •

Chronesthesy – Changes in susceptibility or sensitivity of a target system •

Chrono-therapeutics – Application of chrono-biological principles to the treatment of diseases


Chrono-P’kinetics?? Why study Chrono-P’kinetics?

PK-PD vary with time – Gastric motility: is double in day time than in night – Plasma protein concentrations are higher in day than in night – Hepatic blood flow has been shown to be greatest at 8 am and metabolism to be reduced during the night

• Symptoms of a disease are circadian phase dependent e.g. asthma, angina pectoris, myocardial infarction, ulcer diseases

• Drug toxicity can be avoided/ Minimized by administering at a particular time


Body Rythms


Different types of Rhythms

S. No

Type of Rhythm Example

1. Circadian RhythmsWhich lasts for about one day, like sleep-waking rhythm the body temperature

2. Ultradian RhythmsShorter than a day seconds (like heartbeat)

3. Infradian RhythmsLonger than a day monthly rhythm-menstrual cycle yearly rhythm-bird migration

Examples of circadian rythm Sleep cycle

• Basal gastric acid secretion

• WBC count peak at late night

• Serum cholesterol and triglycerides concentrations are highest early in the evening

• Haemoglobin and insulin are highest in the afternoon

• Intra ocular pressure is highest between 2-4 pm and lowest in late evening

• BP increases in morning after night sleep, peaks afternoon and decreases during sleep

• Potassium efflux from cells is lowest around 3. pm


• AbsorptionAbsorption is altered by circadian changes in gastric empting time gastrointestinal blood flowgastric acid secretion and pH. Most lipophillic drugs seems to be absorbed faster when thedrug is taken in the morning compared with the evening.

Ex: Absorption of valproic acid larger in the morning than in the evening.

• DistributionDistribution is altered by circadian changes in body size and composition blood flow tovarious organs drug protein binding. Peak plasma concentration of plasma proteins likealbumin occurs early in the afternoon, while troughs are found during the night.

Ex: maximum binding of antineoplastics like cisplatin to plasma proteins is in afternoonand minimum in the morning.

• MetabolismMetabolism is altered by circadian changes in liver enzyme activity hepatic bloodflow.

• Ex: For the drugs with low extraction ratio depends on liver enzyme activity and for thedrugs with high extraction ratio depends on hepatic blood flow.

• ExcretionExcretion is altered by circadian changes in gromerular filtration, renal blood flow, uninarypH, tubular reabsorption. All lower during the resting period than in activity period.

Ex: acidic drugs like sodium salicylate excreted quickly after evening than morningadministration.

ASTHMA

• Airway resistance increase during nights

• E. g. Uniphyl a long acting theophylline preparation in the evening

improvement in lung function in the morning

ARTHRITIS

Osteo-arthritis: Less pain in morning and more at night

• Rheumatoid arthritis: pain peaks in morning and decreases as the day progresses.

• NSAID’s for RA after evening meal


Chrono-therapeutic drug delivery

systems

Chronotopic DDs •

Contin •

Pulsincap system •

Ceform •

Time Rx •

Synchrodose •

OROS •

CODAS •

Diffucaps •

Pulsatile drug delivery systems

Erosion based monolithic tables •

Multi particulate systems •

Physicochemical modification of API •

Chronomodulating infusion pumps •

Microchip strategies


CHRONO PHARMACOKINETIC

RESEARCH OF CEFTRIAXONE• Four groups of female rats of 50 - 60 animals each, 28 days old and weighing 100 ± 18 g, were

used.

• The rats were maintained under controlled temperature conditions (22 ± 2 ° C), were well fed

and synchronized with a light-dark cycle with 12 light hours (between 07:00 and 19:00).

• The animals were injected with a single dose of 100 mg ceftriaxone / kg body, at 04:00, 10:00,

16:00 or 22:00, depending on the group they were part of.

Momentul

admin. (h)

kabs

(h-1)

t1/2abs

(h)

kel

(h-1)

t1/2el

(h)

Tlag

(h)

V

(litri)

CLT

(ml/min)

AUC

(μg/ml∙h)

Tmax

(h)

Cmax

(μg/ml)

04:00 19.10 0.036 0.61 1.12 0.073 0.040 0.413 436.00 0.26 240.00

10:00 19.70 0.035 0.64 1.08 0.035 0.027 0.285 536.00 0.21 321.00

16:00 19.80 0.036 0.74 0.93 0.00001 0.033 0.406 423.00 0.17 276.00

22:00 30.60 0.022 1.28 0.54 0.054 0.025 0.532 337.00 0.16 376.00

biopharmacy and pharmacokinetics

Documents