Population PK-PD-PD Modeling of Recombinant Follicle Stimulating Hormone in In Vitro Fertilization/Intracytoplasmic Sperm Injection: Implications on Dosing and Timing of Gonadotrophin Therapy.

This study aimed to characterize an interactive and clinically applicable population pharmacokinetic-pharmacodynamic-pharmacodynamic (PK-PD-PD) model describing follicle-stimulating hormone (FSH)-inhibin B-oocyte relationship in women undergoing assisted reproduction with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The study was a prospective analysis of 25 healthy women undergoing IVF/ICSI using gonadotropin-releasing hormone (GnRH) antagonist protocol. The developed model used the FSH PK profiles to predict both inhibin B (first PD end point) and oocyte retrieval (second PD end point). The modeling framework involved 2 stages. First, the FSH-inhibin B model was developed by the simultaneous approach and applied to estimate the individual area under the inhibin B-time curve (AUC ) at the end of stimulation cycles that varied in length in each woman. In the second stage, the estimated AUC was introduced as a link covariate to predict oocyte retrieval and response category. The population FSH-inhibin B model was described as 3 submodels; PK (exogenous), endogenous, and inhibin B PD models. Weight was the main determinant of both endogenous and exogenous FSH exposures. GnRH antagonist therapy was a significant time-varying covariate when tested against the endogenous FSH production rate (P < .001). AUC could be predicted with women's age and weight. Log-transformed AUC was a significant covariate when tested against oocyte retrieval (P < .001). Simulations concluded a target AUC of 144-303 ng·h/mL for optimal ovarian response. The GnRH antagonist was better started on day 7 of the cycle. Covariate-based dosing suggests lower recombinant follicle-stimulating hormone requirements in a thin and/or young population. An interactive web application "GonadGuide" was developed to facilitate the application in clinical practice.