seminar on noncompartmental pharmacokinetics · bioavailability: bioavailability refers to the...

$: SEMINAR ON NONCOMPARTMENTAL PHARMACOKINETICS · Bioavailability: Bioavailability refers to the fractional dose of a dosage form reaches systemic circulation. For i.v. bolus injection,$
SEMINAR ON

NONCOMPARTMENTALPHARMACOKINETICS

Presented by:Ch. Karthik Siva Chaitanya

M.Pharm (1st sem),PharmaceuticsUCPSc,KU.

1

Contents: Introduction to noncompartmental

pharmacokinetic approachDifferences between compartment and

noncompartment modelsConcepts of noncompartmental model

Statistical moments theory-Mean residence time

Different pharmacokinetic parameters innoncompartment model

Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 2

Noncompartment pharmacokinetics is a newapproach devised to study the time course of drug inthe body with out assuming any compartment model.

Based on the statistical moment theory.

Model independent methodOvercomes some of the drawbacks associated withclassical compartment modeling.Basic assumption is that drug or metabolite followsfirst-order kinetics.


Compartment models Noncompartment models

These require elaborate assumptions tofit the data

Do not require assumptions tocompartment model.

Curve fitting of experimental data usingcomputers. It is a tedious method.

Simple algebraic equations. No curvefitting and no computers

Applicable to linear and nonlinearpharmacokinetics

Applicable to linear pharmacokinetics.

C1 - time profile is regarded asexpressions of exponents

C1 – time profile is regarded asstatistical distribution.

These are useful for most of thesituations, though assumptions ofmodeling are involved.

Particularly useful for the applicationsof clinical pharmacokinetics,bioavailability, and bioequivalencestudies.

Noncompartment and Compartment models – Comparison


Advantages:

Derivation of PK parameters is easy, because of simplealgebraic equations

Mathematical treatment remains same, for drug ormetabolite, provided elimination follows first orderkinetics

Drug disposition kinetics need not be described indetail


Disadvantages:

Information regarding plasma drug concentration-time profile is expressed as an average

Generally not useful for describing the time course ofdrug in the blood

It is applicable only for linear pharmacokinetics


Statistical Moment Theory Statistical moment: A mathematical description of a

discrete distribution of data. Statistical moments calculated from a set of

concentration-time data represent an estimate of thetrue moment (or the true probability density function(PDF)that describes the true relationship betweenconcentration and time). Statistical moment theory provides a unique way to

study time-related changes in macroscopic events. Assume the drug molecules are eliminated according

to a kinetic function, f(t) = C 0e – kt


[AUC]0 = C dt

[AUMC]0 = t x C. dt


Eq.1

2

1 3

I.V. bolus injection – Calculation of AUCand AUMC


Mean residence time(MRT): The term mean residence time (MRT) describes the

average time for all the drug molecules to reside in thebody.


MRT represents the time for 63.2% of drug eliminatedwhen given i.v. bolus injection.

It is analogous to plasma elimination half life, t1/2, i.e.,50% elimination.

Like half life, MRT is a function of both distribution andelimination

For i.v bolus doseCh.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 11

In noncompartmental terms,

k is constant equal to ratio of clearance to Vss Vss is volume of distribution at steady state

t1/2 = 0.693MRTMRTiv is used for comparison. For eg: following

constant rate of infusion

Where T = duration of infusion

0.693Plasma elimination half life : t1/2 = k10


DRUG ABSORPTION: MAT(Mean absorption time) is defined as the

differences in mean residence time (MRT) afterdifferent modesof administration.

MAT = MRTni – MRTiv

MRTni = mean residence time of drug by non-instantaneous route, h

MRTiv = mean residence time of drug by i.v.bolus injection

Same equation is used for i.m. injectionCh.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 13

When absorption follows zero order

T = time over which absorption takes place, h

MAT can be used for comparision of dosage formsCh.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 14

OTHER APPLICATIONS OF MRT Mean Dissolution Time(MDT)

MDT=MRTtest-MRTsoln In oral administration,

MRToral=MRTiv+1/Ka For evaluation of absorption data,

MAT=MRTtest-MRTivMAT=1/KaKa is first order absorption rate constant


Drug Clearance:• After iv bolus administration,

•At steady state after constant rate iv infusion

•By using extraction ratio Cl=Q(ER)

Ko is rate of infusion ; Css is steady state concentration


APPARENTVOLUME OF DISTRIBUTION: Vss is volume of distribution at steady state

independent of elimination Vss =i.v dose(AUMC)/(AUC) If drug is given by constant rate i.v infusion

Where Ko is infusion rate; is duration of infusion


Steady State Plasma Drug Concentration:

The Css is a function of the effective rateof dosing andtotal body clearance of thedrug in a patient


F is fraction bioavailable

AUCss is AUC from t=0 to t= during a dosingintervalat steady state


•Method of superposition is used for predicting steady stateconcentration on repetitive dosing from data obtainedafter a single dose.

Predicting the Time to Steady State:

Time required for the drug to reach steady state, i.e.,99%, takes 6.65 half lives.

In extravascular route (or prolongedrelease drugproducts), the time requiredto attain ss takes longerthan predicted bybiological half life

In multicompartment disposition, timerequired toattain to ss is shorter than that predicted by terminalhalf life


In noncompartmentmodels, when the drugisadministered repetitive dosing, fss

AUC = area under the curve in single dose


Bioavailability: Bioavailability refers to the fractional dose of a dosage

form reaches systemic circulation.For i.v. bolus injection, bioavailability is referred as

unity (=1) Bioavailability (F) of a dosage form


Fraction metabolised:AUCx

1

Fraction metabolized, Fm =AUC1

• AUCx1 is area under the curve of metabolite

concentrationin plasma versus time from zero toinfinity

• AUC1 is the total area under the metaboliteconcentration –time curve after a equimolarintravenous dose of a metabolite


CONCLUSION: The noncompartmental pharmacokinetic methods

permit a comprehensive pharmacokinetic analysiswith out resort to curve fitting,sophisticatedcomputers or tedious mathematical equations.

Although these methods cannot be applied to allpharmacokinetic problems,they are useful for mostproblems and are particularly useful for the clinicalapplication of pharmacokinetics.


References: Milo Gibaldi , Biopharmaceutics and clinical

pharmacokinetics, 4th edition ,pg no 17-26 D.Perrier,M.Gibaldi Pharmacokinetics, 2nd edition ,

pg no 409-417 Leon Shargel ,Applied biopharmaceutics and

pharmacokinetics,5th edition,pg no 717-753 V.Venkateshwarlu,Biopharmaceutics and

pharmacokinetics, pg no 309-330 www.pharainfo.net


THANK YOU


seminar on noncompartmental pharmacokinetics · bioavailability: bioavailability refers to the...

Documents