Petricoul O.(1), Nguyen Q.T.X.(2), Decosterd G.(2), Loumaye E.(2), Munafo A.(2)
(1) EMF Consulting, Aix-en-Provence, France; (2) Serono International SA, Geneva, Switzerland
Background. Iturelix (Antide) has been shown to be effective for postponing the mid-cycle Luteinising Hormone (LH) surge in healthy female. It was then intended to assess Antide’s efficacy in patients undergoing In Vitro Fertilisation and Embryo Transfer (IVF-ET). Objectives. The purpose of this analysis was to describe the pharmacokinetic (PK) profile of Antide in patients undergoing multiple follicular development and to assess the relationship between Antide serum levels and LH serum levels. Methods. Data were collected during a phase II, dose ranging study. One hundred and forty eight patients received subcutaneously (SC) either Antide 1mg/1mL BID, or once daily 1mg/1mL, 0.5 mg/0.5mL, 0.5 mg/1mL, 0.25 mg/1mL or 0.1 mg/1mL. The treatment groups were chronologically initiated, and any dose group was terminated when 2 subjects per group exhibited LH surge. PK and PK/PD population modelling, using NONMEM version V, were used to describe concentrations of Antide and effect of Antide concentrations on LH serum levels. Results. A two-compartment disposition model with first order absorption and first order elimination best described the pharmacokinetics of Antide. The absorption of the drug was very rapid. The relative bioavailibility was found to vary between the treatment groups. It appeared that Antide’s bioavailability increased when concentration of drug in the syringe decreased. Finally, body weight was found to linearly affect the apparent clearance and the apparent central volume. Antide caused an immediate decrease of baseline LH serum levels. In only a total of 4 women did an LH surge occur (2 in the group 0.5 mg/0.5 mL and 2 in the group 0.25 mg/1 mL). A turnover model best described the LH serum concentrations, with a global inhibition of LH secretion due to Antide concentrations. Since there was no data in this study to describe the LH kinetics during a complete normal menstrual cycle, the drug effect on LH surge was difficult to assess. Conclusions. The PK/PD model developed during this analysis allowed predicting the inhibition of LH secretion by Iturelix in patients undergoing multiple follicular development for assisted reproductive technology with recombinant human Follicle Stimulating Hormone.
Reference: PAGE 10 (2001) Abstr 197 [www.page-meeting.org/?abstract=197]
Poster: poster