Dose selection of corifollitropin alfa by modeling and simulation in controlled ovarian stimulation.
In controlled ovarian stimulation (COS), a single subcutaneous dose of corifollitropin alfa is used to initiate and sustain multifollicular growth for 7 days. The objective of this study was to determine the optimal dose of corifollitropin alfa. A pharmacokinetic model was developed to describe the time profile of corifollitropin alfa concentrations. Multiple parameters reflecting ovarian response were included in a pharmacokinetic-pharmacodynamic (PK-PD) model framework. An early decline in serum inhibin B was shown to be a sensitive marker for COS failure. Simulations were performed to select the lowest corifollitropin alfa dose that would result in a minimal cancellation rate: 100 microg for a group of women weighing <or=60 kg and 150 microg for a group of women weighing >60 kg. With these doses, the predicted mean number of oocytes per started COS cycle was similar in the two groups, i.e., 12.1 and 13.2, respectively. The selected doses were tested in prospective clinical trials and were proven to be adequate.
de Greef
R
R
Global Drug Metabolism & Pharmacokinetics, Merck Research Labs, Merck Sharp & Dohme, Oss, The Netherlands.
Zandvliet
A S
AS
de Haan
A F J
AF
Ijzerman-Boon
P C
PC
Marintcheva-Petrova
M
M
Mannaerts
B M J L
BM
D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D043373:Follicle Stimulating Hormone, Human / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007265:Inhibins / Q000378:metabolism; D015233:Models, Statistical; D009865:Oocytes / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects; D010053:Ovary / Q000187:drug effects*; D013268:Stimulation, Chemical
D043373:Follicle Stimulating Hormone, Human; C437186:follicle stimulating hormone, human, with HCG C-terminal peptide; C422364:inhibin B; D007987:Gonadotropin-Releasing Hormone; D007265:Inhibins