Trine Høyer Rose (1,2), Daniel Röshammar (1), Mats O. Karlsson (3), Johnny T. Ottesen (2)
(1) Experimental Medicine, Ferring Pharmaceuticals A/S, Denmark (2) Department of Science, Systems and Models, Roskilde University, Denmark (3) Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: A recombinant follicle stimulating hormone (FSH) expressed from a cell-line of human fetal retinal origin (PER.C6®), FE 999049, is currently under development at Ferring Pharmaceuticals and is intended to be used in infertility treatment for controlled ovarian stimulation. The objective of the present analysis was to characterise the FE 999049 dose-inhibin B-response using a semi-mechanistic model based approach. In addition the aim was to use the model to improve precision of inhibin B predictions, a potential marker of ovarian response to gonadotropin treatment for controlled ovarian stimulation, compared to estimates obtained with traditional statistical methods.
Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model describing the FE 999049 concentration-time profile and inhibin B levels after multiple doses of FE 999049 was developed based on data from a phase II clinical study including 222 infertile women. The pharmacokinetic model development was supported by model results and parameters from a phase I study. The PKPD model structure was based on the underlying physiology for the hormonal dynamics of FSH and inhibin B in the reproductive endocrine system, and adjusted in accordance with the clinical study protocol and observed data. The model was implemented in NONMEM 7.2.0 and graphical presentations were performed in R.
Results: The FE 999049 pharmacokinetics were described using a one compartment model with first order absorption and a transit compartment for a delayed absorption. The endogenous FSH levels were not down-regulated in the women prior to stimulation and were therefore included in the model as an extra input to the central compartment. Using the total FSH concentration the PK model was linked to an indirect stimulatory response model for inhibin B levels with a negative feedback loop to the endogenous FSH production.
Conclusions: The semi-mechanistic PKPD model for the FE 999049 dose-inhibin B-response relationship was shown to improve precision of inhibin B prediction compared to when using an empirical dose-response model or confidence intervals obtained with traditional statistical methods.
Reference: PAGE 23 (2014) Abstr 3232 [www.page-meeting.org/?abstract=3232]
Poster: Drug/Disease modeling - Endocrine