Achiel Van Peer, Ph.D. Clinical Pharmacology

1 Gent, 24 August 2007/avpeer1 Basic Concepts of PharmacokineticsAchiel Van Peer, PharmacologyGent, 24 August 2007/avpeer2 Some introductory ExamplesGent, 24 August 2007/avpeer315 mg of Drug X in a slow release OROS capsuleadministered in fasting en fed conditions in comparison to 15 mg in solution fastingGent, 24 August 2007/avpeer4 Prediction of drug plasma concentrations before the first dose in a humanNOAEL in female ratNOAEL in male ratNOAEL in female dogNOAEL in male dogFirst dose 5 mg Fabs 100%Fabs 50%Fabs 20% Gent, 24 August 2007/avpeer5 Allometric ScalingGent, 24 August 2007/avpeer6 Pharmacokinetics: Time Profile of Drug Amounts Drug at absorption siteDrug in bodyMetabolitesExcreted drugTime (arbitrary units)Percent of doseRowland and Tozer, Clinical Pharmacokinetics: Concepts and Applications, 3rdEd.

2 1995 Gent, 24 August 2007/avpeer7 Definition of Pharmacokinetics ? Pharmacokinetics is the science describing drugabsorption from the administration sitedistribution to tissues, target sites of desired and/or undesired activitymetabolismexcretionPK= ADMEGent, 24 August 2007/avpeer8We will coverSome introductory Examples Model-independent ApproachCompartmental ApproachesDrug Distribution and EliminationMultiple-Dose PharmacokineticsDrug Absorption and Oral BioavailabilityRole of PharmacokineticsGent, 24 August 2007/avpeer9 The simplest approach .. observational pharmacokineticsThe Model-independent ApproachCmax : maximum observed concentrationTmax : time of CmaxAUC : area under the curveGent, 24 August 2007/avpeer10 Cmax, Tmaxand AUC in Bioavailability and Bioequivalence StudiesAbsolute bioavailability (Fabs) compares the amount in the systemic circulation after intravenous (reference) and extravascular (usually oral) dosingFabs = AUCpo/AUCivfor the same dose between 0 and 100% (occasionally >100%)Relative bioavailability (Frel) compares one drug product ( tablet) relative to another drug product (solution)Bioequivalence (BE).

3 A particular FrelTwo drug products with the same absorption rate (Cmax, Tmax) and the same extent (AUC) of absorption (90% confidence intervals for Frel between 80-125%)Gent, 24 August 2007/avpeer11 Absolute oral bioavailabilityflunarizine, J&J data on fileOther example: nebivolol: 10% in extensive metabolisers; 100% in poor metabolisersGent, 24 August 2007/avpeer12 Area under the curve)12).(221(AUCt2-t1ttCC +=Trapezoidal rule: divide the plasma concentration-time profile to several trapezoids, and add the AUCs of these trapezoidsConcTimezClastlatedAUCextrapo =00 Units, , 24 August 2007/avpeer13 Elimination half-life ?Half-life (t1/2) : time the drug concentration needs to decrease by 50%Gent, 24 August 2007/avpeer14 Elimination half-life ?

4 Visual inspectionGent, 24 August 2007/avpeer15 Elimination half-life ?visual inspection or alternatives ?Half-life (t1/2) : time to decrease by 50%T1/2 = 6 hrsDerived from a semilog plotT1/2 = zGent, 24 August 2007/avpeer16 From Whole-Body Physiologically based Pharmacokinetics to CompartmentalModelsPoggesi et al., Nerviano Medical Science Gent, 24 August 2007/avpeer17 Compartmental ApproachOne-compartment PK model BodycompartmentDrug AbsorptionDrug Eliminationdrug distributes very rapidly to all tissues via the systemic circulation an equilibrium is rapidly established between the blood and the tissues, the body behaves like one (lumped) compartmentdoes not mean that the concentrations in the different tissues are the same Gent, 24 August 2007/avpeer18 One compartment behaviour more often observed after oral drug intake 1101001000081624324048 Time, hoursPoor metabolisersExtensive metabolisersGent, 24 August 2007/avpeer19 Intravenous dose of mg Levocabastine(J&J data on file)

5 Gent, 24 August 2007/avpeer20 Depending on rate of equilibration with the systemic circulation, lumping tissues together,and simplification is possibleMulti-Tissue or Multi-Compartment Whole Body Pharmacokinetic modelTri-compartment modelTwo-compartment modelOne-compartment modelGent, 24 August 2007/avpeer21 Zero-order rate drug administration and first-order rate drug eliminationInfusion rate mg/minRate of elimination is proportional to the Amount in blood/plasmadDose/dt = Ko = mg/mindA/dt = A in blood, plasma[Often K=Kel=K10]Gent, 24 August 2007/avpeer22 First-order rate of drug disappearanceIntravenous bolusAmount A [or Concentration C]in blood, plasmaRate of elimination is proportional to the Amount or Concentration in blood, plasmadA/dt = = A = Amount in plasma, then V= Plasma volumeIf A = Remaining amount in the body, thenVd= Total volume of distributionGent, 24 August 2007/avpeer23A single iv dose of 5 mgfor a drug with immediate equilibration (one compartment behaviour)dC/dt = = = = = = C0.

6 , 24 August 2007/avpeer24A single iv dose of 5 mgC = = for log10scale: slope = k10 , 24 August 2007/avpeer25A single iv dose of 5 mgln C = = =C2= half of C1 Slope=k10= the elimination rate constantHalf-life = , 24 August 2007/avpeer26A single iv dose of 5 mgVd = volume of distribution,relates the drug concentrationto the drug amountin the , 24 August 2007/avpeer27 One-Compartment model after intravenous administrationVd = volume of distribution,relates the drug concentration at a particular timeto the drug amount in the body at that timek10= (first-order) elimination rate constantClearance (CL) = volume of drug in the body cleared per unit timeHalf-life = . Vd/CL Gent, 24 August 2007/avpeer28 Compartmental Approachafter intravenous dosingRapidly equilibrating tissues:plasma, red blood cells, liver, kidney.

7 Slower equilibrating:adipose tissues, muscle, ..Usually peripheral compartmentSlowly redistribution reason for long terminal half-lifeEliminationDistributionRe-distr ibutionCentral compartmentPeripheralcompartmentGent, 24 August 2007/avpeer29 Intravenous dose of mg levocabastineV1 = 44 LV2 = 35 LK12= h-1K21= h-1K10= h-1 Gent, 24 August 2007/avpeer30 Intravenous dose of mg levocabastineV1 = 44 LV2 = 35 LCld= L/hCld= L/hCl= L/h=30 mL/minVdss = V1 + V2 Gent, 24 August 2007/avpeer31 Rates of drug exchangeDAp/dt = - - + = - very fast decaydue to distribution to tissues and elimination ( distribution phase ) until equilibrium is reached (influx into and efflux from tissue is equal)

8 After a pseudo-equilibrium is reached, there is only loss of drug from the body ( elimination phase ), but is in fact combination of redistribution from tissues and eliminationRate of redistribution may differ significantly across drugs; long terminal half-life is compounds sticks somewhereGent, 24 August 2007/avpeer32 Intravenous dose of mg levocabastineCp= .t+ .tCp= .t+ = Vd = CL/ =Dose/(AUC. )=VdareaGent, 24 August 2007/avpeer33 Two-compartmental modelCentral CompartmentVcPeripheralCompartmentVtK10K 12K21K10, K12, K21 are first order rate constantshybrid first-order rate constants and for the so-called distribution phase and elimination phases, T1/2 and T1/2 Vc, Vdss, Vd or Vdarea are Vd of central compartment, at steady-state, during elimination phaseGent, 24 August 2007/avpeer34 Compartmental approachafter intravenous dosingCentral compartmentShallow PeripheralcompartmentDeep PeripheralcompartmentCompartments serve as reservoirs with different drug amounts (concentrations)

9 ,different volumes, and different rates of exchange of drug with the central shape of the plasma concentration-time profile empirically defines the number of compartmentslGent, 24 August 2007/avpeer35 Intravenous SufentanilGepts et al., Anesthesiology, 83:1194-1204, 1995 Gent, 24 August 2007/avpeer36 Three compartmental modelSufentanil PharmacokineticsGepts et al., Anesthesiology, 83:1194-1204, 1995 Mixed-effects Population PK analysis (N =23)Population Average CV (%)Volume of distribution (L)Central (V1) equilibrating (V2)6631 Slowly equilibrating (V3)60876At steady-state689 Clearance (L/min)Systemic (CL or CL1) distribution (CL2) distribution (CL3) , 24 August 2007/avpeer37 Three compartmental modelSufentanil PharmacokineticsGepts et al.

10 , Anesthesiology, 83:1194-1204, 1995 Fractional CoefficientsRate constants (min-1) (min-1)Half-lives (min) 59 1129 Gent, 24 August 2007/avpeer38 Compartmental approachafter intravenous dosingCentral compartmentShallow PeripheralcompartmentCentral compartmentDeep PeripheralcompartmentPeripheralcompartme ntEffect siteGent, 24 August 2007/avpeer39 Shafer and Varvel, Anesthesiology 74:53-63, 1991 Time profile of opioid concentrations in plasma and the predicted concentrations at the effect site based upon an effect compartment PK-PD model(expressed as percentage of the initial plasma concentration)Effect site concentration profile reflect difference in onset time of analgesiaGent, 24 August 2007/avpeer40 Rate of Drug Distributionperfusion-limitedtissue distribution immediate equilibrium of drug in blood and in tissue only limited by blood flow highly perfused : liver, kidneys, lung, brain poorly perfused.