seminar on noncompartmental pharmacokinetics · bioavailability: bioavailability refers to the...
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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.
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 3
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 4
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 5
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 6
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 7
I.V. bolus injection – Calculation of AUCand AUMC
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 9
Mean residence time(MRT): The term mean residence time (MRT) describes the
average time for all the drug molecules to reside in thebody.
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 10
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 12
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 15
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 16
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 17
Steady State Plasma Drug Concentration:
The Css is a function of the effective rateof dosing andtotal body clearance of thedrug in a patient
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 18
F is fraction bioavailable
AUCss is AUC from t=0 to t= during a dosingintervalat steady state
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 19
•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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 20
In noncompartmentmodels, when the drugisadministered repetitive dosing, fss
AUC = area under the curve in single dose
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 21
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 22
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 23
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.
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 24
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
Ch.Karthik SivaChaitanya,M.Pharm 1stSem,UCPSc,KU 25