title: Population pharmacokinetic analysis of pegylated human erythropoietin in rats.
abstract: The purpose of this study was to model the pharmacokinetics of the pegylated human erythropoietin (PEG-EPO) after single-dose administration in rats, and to evaluate the influence of weight, sex, and pregnancy status on the pharmacokinetic parameters. A total of 436 serum concentrations from 193 Sprague-Dawley rats were obtained from four pharmacokinetic/toxicokinetic studies, in which a single dose of PEG-EPO was administered by the intravenous (i.v.; dose range: 2.5 to 500 microg/kg) and subcutaneous (s.c.; dose range: 12.5 to 500 microg/kg) route. Pharmacokinetic analysis was performed using nonlinear mixed effect modeling (NONMEM V software) to determine the population mean of pharmacokinetic parameters and the variances of the interindividual random effects. The effect of weight, sex, and pregnancy status on the pharmacokinetic parameters was evaluated by forward inclusion and backward elimination process, using the likelihood ratio test. Nonparametric bootstrap analysis was employed as an internal model evaluation technique to qualify the model developed. An open two-compartment model with linear elimination from the central compartment, a first-order absorption with lag time characterized the serum concentration-time profiles of PEG-EPO after i.v. and s.c. administration. For a male rat of 0.24 kg, the average CL, Vc, Q, Vp, Ka, Tlag, and F was estimated to be 0.728 mL/h, 15.8 mL, 0.373 mL/h, 6.99 mL, 0.0618 h(-1), 3.13 h, and 48.8%, respectively. A twofold increase in weight corresponded with a 170 and 238% increase in CL and Vc, respectively. In female rats, Vp was reduced by 11%, whereas F was increased by 15%. No effect of pregnancy status on any of the parameters could be identified. The interindividual variability in CL, Vc, Vp, Ka, and F was estimated at 10.7, 14.7, 16.6, 11.0, and 13.6%, respectively. Nonparametric bootstrap analysis confirmed the accuracy and the precision of the NONMEM parameter estimates. A population pharmacokinetic approach was used to integrate the knowledge gathered from several pharmacokinetic/toxicokinetic studies in rats. The pharmacokinetics of PEG-EPO in the rat was successfully modeled using a two-compartmental model with a linear elimination from the central compartment and a first-order absorption process with lag time. Weight and sex, but not pregnancy status, were identified as covariates of interest during preclinical development. The population pharmacokinetic model developed will be further used for the purpose of interspecies scaling and PK/PD modeling.
authors.affiliation: Advanced PK/PD Modeling and Simulation department, Global Clinical Pharmacokinetics and Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research & Development (a division of Janssen Pharmaceutica NV), 2340 Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Jolling
authors.forename: Juan Jose Perez
authors.initials: JJ
authors.lastname: Ruixo
authors.forename: Alex
authors.initials: A
authors.lastname: Hemeryck
authors.forename: Vladimir
authors.initials: V
authors.lastname: Piotrovskij
authors.forename: Tony
authors.initials: T
authors.lastname: Greway
mesh_terms: D000818:Animals; D004921:Erythropoietin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004921:Erythropoietin; D011092:Polyethylene Glycols