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 (AUCInhb) at the end of stimulation cycles that varied in length in each woman. In the second stage, the estimated AUCInhb 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). AUCInhb could be predicted with women's age and weight. Log‐transformed AUCInhb was a significant covariate when tested against oocyte retrieval (P < .001). Simulations concluded a target AUCInhb 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.