Population pharmacokinetic/pharmacodynamic modeling of cetrorelix, a novel LH-RH antagonist, and testosterone in rats and dogs.
OBJECTIVE
Population models for the pharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasing hormone (LH-RH) antagonist, and the pharmacodynamic response on testosterone production were investigated in rats and dogs.


METHODS
The plasma concentrations of CET and testosterone were determined after intravenous and subcutaneous injections. The population PK/PD-models were developed using P-PHARM software.


RESULTS
Absolute bioavailability of cetrorelix was 100% in rats and 97% in dogs. In rats, the pharmacokinetics was explained by a two-compartment model with saturable absorption, while a three-compartment model was used in dogs. Testosterone suppression in both species was described by a sigmoid E(max) model with maximum effect (E(max)) considered as total hormonal suppression. The duration of testosterone suppression in rats was longer at higher doses. The population elimination half-lives after iv-dose were 3.0 h in rats and 9.3 h in dogs. Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in rats and dogs, respectively.


CONCLUSIONS
A population pharmacokinetic model was developed to explain the dissolution rate limited absorption from the injection site. The suppression of testosterone could be described by an indirect inhibitory sigmoid E(max) model. In both species 1-2 ng/ml CET in plasma was necessary to suppress testosterone production.
Schwahn
M
M
Department of Biological Research Biochemistry, Corporate Research & Development, ASTA Medica Group, Frankfurt/Main, Germany. martin.schwahn@astamedica.de
Nagaraja
N V
NV
Derendorf
H
H
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood / Q000493:pharmacokinetics*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D006727:Hormone Antagonists / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D013739:Testosterone / Q000097:blood / Q000493:pharmacokinetics*
D012739:Gonadal Steroid Hormones; D006727:Hormone Antagonists; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C062876:cetrorelix