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 14 2010
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PK/PD Modeling of Therapeutic Effects of Erythropoietin
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 14 2010. - PowerPoint PPT Presentation
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PK/PD Modeling of Therapeutic Effects of Erythropoietin
Wojciech Krzyzanski, PhD, MADepartment of Pharmaceutical Sciences
University at Buffalo
Semiparametric Bayesian Inference: Applications in Pharmacokinetics and Pharmacodynamics
SAMSI, Research Triangle Park, July 14 2010
General Model of Hematopiesis
From Kaushansky, N. Engl. J. Med. 354:2034 (2006).
Regulation of Erythropoiesis
Wolber and Jelkmann., News Physiol. Sci. 17: 6 (2002)
Red blood cells(O2-capacity, arterial pO2)
pO2-dependent production
Kidney
Erythropoietin(EPO)
Bone marrow
+
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
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.
KD ~ 100-200 pM
Internalization rate ~ 0.7 h-1
300- 1000 receptors per erythroid cell
Time (hr)0 80 160 240 320 400
rHu
EP
O c
on
cen
trat
ion
(IU
/l)
1
10
100
1000
10000300 IU/kg600 IU/kg1200 IU/kg2400 IU/kg
rHuEPO Pharmacokinetics
Ramakrishnan et al., J. Clin. Pharmacol. 44:991-1002 (2004).
Flaharty et al., Clin. Pharmacol. Ther. 47: 557-64 (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 = 0.4-1. Slow absorption from the injection site: flip-flop kinetics.
rHuEPO Pharmacodynamics
0 5 10 15 20 25
Ret
icu
locy
tes,
%
1
2
3
4
5
0 5 10 15 20 25
RB
C C
ou
nt,
10
12 c
ells
/L
4.5
4.8
5.1
5.4
Time, days
0 5 10 15 20 25
Hem
og
lob
in,
g/d
L
14
15
16
Time, days
0 7 14 21 28
Ser
um
EP
O, I
U/L
10
100
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 26:295-306 (2005).
PK/PD Modeling Paradigm
Mager and Jusko, Clin. Pharmacol. Ther. 70:210-16 (2001).
Receptor Mediated EPO Endocytosis and Degradation
Gross and Lodish, J. Biol. Chem. 281:2024 (2006).
DIV
DPO, F•kaKo, TINF
SerumCpVc
TissueDT
ReceptorComplex
DR
kon
koff
kel km
kpt
ktp
FreeReceptor[Rmax-DR]
kdeg
ksyn
+
Target-Mediated Drug Disposition
DRkkCpDRRkdt
dDR
DRkCpDRRkVc
DkCpkk)t(In
dt
dCp
moffmaxon
offmaxonT
tpptel
Mager and Jusko. J Pharmacokinet Pharmacodyn. 28:507-32 (2001)