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PK/PD Modeling of Therapeutic Effects of Erythropoietin Wojciech Krzyzanski, PhD, MA Department of Pharmaceutical Sciences University at Buffalo Semiparametric.

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Presentation on theme: "PK/PD Modeling of Therapeutic Effects of Erythropoietin Wojciech Krzyzanski, PhD, MA Department of Pharmaceutical Sciences University at Buffalo Semiparametric."— Presentation transcript:

1 PK/PD Modeling of Therapeutic Effects of Erythropoietin Wojciech Krzyzanski, PhD, MA Department of Pharmaceutical Sciences University at Buffalo Semiparametric Bayesian Inference: Applications in Pharmacokinetics and Pharmacodynamics SAMSI, Research Triangle Park, July

2 General Model of Hematopiesis From Kaushansky, N. Engl. J. Med. 354:2034 (2006).

3 Regulation of Erythropoiesis Wolber and Jelkmann., News Physiol. Sci. 17: 6 (2002) Red blood cells (O 2 -capacity, arterial pO 2 ) pO 2 -dependent production Kidney Erythropoietin (EPO) Bone marrow +

4 Erythropoietin 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

5 Erythropoietin Receptor Sawyer et al., JBC 262: 5554 (1987); Broudy et al., Blood 77: 2583 (1991) 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. K D ~ pM Internalization rate ~ 0.7 h receptors per erythroid cell

6 rHuEPO Pharmacokinetics Ramakrishnan et al., J. Clin. Pharmacol. 44: (2004). IV SC Flaharty et al., Clin. Pharmacol. Ther. 47: (1990). Distribution: 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.

7 rHuEPO Pharmacodynamics rHuEPO was administered SC to healthy subjects 150 IU/kg t.i.w for four weeks. rHuEPO pharmacodynamic responses Reticuloctyte count RBC Hemoglobin concentration Krzyzanski et al., EJPS 26: (2005).

8 PK/PD Modeling Paradigm Mager and Jusko, Clin. Pharmacol. Ther. 70: (2001).

9 Receptor Mediated EPO Endocytosis and Degradation Gross and Lodish, J. Biol. Chem. 281:2024 (2006).

10 D IV D PO, Fka Ko, T INF Serum Cp Vc Tissue D T Receptor Complex DR k on k off k el kmkm k pt k tp Free Receptor [R max -DR] k deg k syn + Target-Mediated Drug Disposition Mager and Jusko. J Pharmacokinet Pharmacodyn. 28: (2001)

11 Erythropoietic Cascade Stem Cell BFU-e CFU-e ProerythroblastErythroblast Reticulocyte RBC EPO responsive cells EPOR- /+ EPOR++ + EPOR+ EPOR- EPOR+/- EPOR- EPOR-

12 Lifespan Distribution Cell lifespan - time a cell remains in the population Mean lifespan-population mean of the lifespan distribution

13 Lifespan Controlled Cell Loss Point Lifespan Distribution: (t) = (t-T R ) (k in * )(t) = k in (t-T R )

14 Basic Model: Stimulation of k in Baseline: R 0 = k in ·T R Krzyzanski and Jusko, JPB 27: 467 (1999).

15 PK/PD of rHuEPO in Rats Mean 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).

16 TMDD PK/PD Model of rHuEPO Woo et al., JPP 34: (2007).

17 PK/PD Model Equations Woo et al., JPP 34: (2007).

18 PK/PD Model Equations Woo et al., JPP 34: (2007).

19 Initial Conditions, for t < 0, and, for t 0 Woo et al., JPP 34: (2007).

20 Baseline Equations Woo et al., JPP 34: (2007).

21 Residual Error Variance Model Parameter estimates were obtained by minimizing the -2LL objective function in ADAPT II. Woo et al., JPP 34: (2007).

22 Parameter Estimates ParameterEstimate CV% V p (ml/kg) k el (h -1 ) k pt (h -1 ) k tp (h -1 ) k int (h -1 ) k deg (h -1 ) k on (nM -1 h -1 ) K D (nM) R 0 (nM) C 0 (nM) 0a0a RBC 0 (10 6 cells/ l) a MCH (pg/cell)20.0 a T P1 (h) T P2 (h) T RET (h) T RBC (h)1440 a S max SC 50 (pM) I max 1.0 a IC 50 (g/dl) a Parameter was fixed. Woo et al., JPP 34: (2007).

23 Numerical Challenges Stiffness: Receptor binding (k on, R 0 ) is typically much faster than distribution and elimination (k el,k tp,k pt ). Delay differential equations: Lifespan based PD model requires a DDE solver.

24 Parameter 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.

25 Conclusions rHuEPO 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.

26 Acknowledgments Sukyung Woo, PhD. William Jusko, PhD.


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