Presentation on theme: "PK/PD Modeling of Therapeutic Effects of Erythropoietin"— Presentation transcript:
1PK/PD Modeling of Therapeutic Effects of Erythropoietin Wojciech Krzyzanski, PhD, MADepartment of Pharmaceutical SciencesUniversity at BuffaloSemiparametric Bayesian Inference: Applications in Pharmacokinetics and PharmacodynamicsSAMSI, Research Triangle Park, July
2General Model of Hematopiesis From Kaushansky, N. Engl. J. Med. 354:2034 (2006).
3Regulation of Erythropoiesis Red blood cells(O2-capacity, arterial pO2)pO2-dependent productionKidneyErythropoietin(EPO)Bone marrow+Wolber and Jelkmann., News Physiol. Sci. 17: 6 (2002)
4Erythropoietin EPO is a 30.4 kD glycoprotein responsible for survival, proliferation, and maturation of erythroid cells. EPO is produced by peritubal cells in the kidneys in response to tissue hypoxia. Indications for rHuEPO:- Anemia of chronic renal failure- Chemotherapy induced anemia- Anemia of prematurity
5Erythropoietin Receptor EPOR is a 185 kD member of the class 1 cytokine receptor superfamily. Expressed on erythroid progenitor cells, epicardium, neurons, liver, gut, endothelium. Upon binding to EPO homodimerizes and activates JAK2 tyrosine kinase. EPO-EPOR complex is internalized and degraded by the endosome-lysosome pathway. KD ~ pM Internalization rate ~ 0.7 h-1 receptors per erythroid cellSawyer et al., JBC 262: 5554 (1987); Broudy et al., Blood 77: 2583 (1991)
6rHuEPO Pharmacokinetics Time (hr)80160240320400rHuEPO concentration (IU/l)110100100010000300 IU/kg600 IU/kg1200 IU/kg2400 IU/kgSCIVDistribution: Vd = 3-5 L. Moderate nonlinear clearance: t1/2 = 4-11 hr. Minimal renal and hepatic clearance. Receptor binding, internalization, and degradation in bone marrow.Dose dependent bioavailability: F =Slow absorption from the injection site: flip-flop kinetics.Flaharty et al., Clin. Pharmacol. Ther. 47: (1990).Ramakrishnan et al., J. Clin. Pharmacol. 44: (2004).
7rHuEPO Pharmacodynamics rHuEPO was administered SC to healthy subjects 150 IU/kg t.i.w for four weeks.rHuEPO pharmacodynamic responsesReticuloctyte countRBCHemoglobin concentrationKrzyzanski et al., EJPS 26: (2005).
12Lifespan Distribution Cell lifespan - time a cell remains in the populationMean lifespan-population mean of the lifespandistribution
13Lifespan Controlled Cell Loss Point Lifespan Distribution: (t) = (t-TR)(kin* )(t) = kin(t-TR)
14Basic Model: Stimulation of kin Baseline: R0 = kin·TRKrzyzanski and Jusko, JPB 27: 467 (1999).
15PK/PD of rHuEPO in RatsMean serum rHuEPO concentrations, reticulocyte, and hemoglobin levels following IV bolus administration of 10, 100, 450, 1350, and 4050 IU/kg in rats.Woo et al., JPP 34: (2007).
16TMDD PK/PD Model of rHuEPO Woo et al., JPP 34: (2007).
17PK/PD Model EquationsWoo et al., JPP 34: (2007).
18PK/PD Model EquationsWoo et al., JPP 34: (2007).
19Initial Conditions , for t < 0, and , for t 0 , for t 0 Woo et al., JPP 34: (2007).
21Residual Error Variance Model Parameter estimates were obtained by minimizing the -2LL objective function in ADAPT II.Woo et al., JPP 34: (2007).
22Parameter Estimates a Parameter was fixed. Parameter Estimate CV% Vp (ml/kg)56.941kel (h-1)0.22562kpt (h-1)0.20926ktp (h-1)0.1721kint (h-1)0.822866kdeg (h-1)0.113358kon (nM-1h-1)11.3280KD (nM)1.29770R0 (nM)0.063243C0 (nM)0aRBC0 (106 cells/l)6.128aMCH (pg/cell)20.0aTP1 (h)42.978TP2 (h)3.0275TRET (h)72.334TRBC (h)1440aSmax3.487SC50 (pM)1.735Imax1.0aIC50 (g/dl)1.7910a Parameter was fixed.Woo et al., JPP 34: (2007).
23Numerical ChallengesStiffness: Receptor binding (kon, R0) is typically much faster than distribution and elimination (kel,ktp,kpt).Delay differential equations: Lifespan based PD model requires a DDE solver.
24Parameter Estimability Large number of model parameters.Observable data (blood compartments) are poorly informative about processes occurring in the bone marrow: receptor binding, cell maturation, negative feedback.Large values of SE of corresponding parameter estimates, correlations, singularity of covariance matrix.Necessary reduction of the number of model parameters:- fixing at known physiological values.- simplifying assumptions: quasi steady-state etc.
25ConclusionsrHuEPO nonlinear PK can be explained by receptor mediated disposition.PD response is significantly delayed with respect to PK exposure.PK/PD model exhibits stiffness and requires DDE solver.System large dimension and data based on blood measurements lead to parameter estimability problems.