Taright N. (1), Mentré F. (1), Engrand P. (2), Loumaye E. (2), Trinchard-Lugan I. (2), Munafo A. (2).
(1)INSERM U 436, Paris, France (2)ARES-SERONO International, Geneva, Switzerland
Population pharmacokinetics of recombinant human luteinising hormone (r-hLH) was investi- gated during a four-arm phase II trial, during which r-hLH was used for triggering final follicular maturation in women undergoing In Vitro Fertilisation treatment. r-hLH was administred as a single SC injection the day after the last r-hFSH administration when one follicle reached 18 mm and more than 2 follicles 16 mm. Four doses of r-hLH were assessed: 5000 IU, 15000 IU, 30000 IU or 25000 IU (15000 IU followed by 10000 IU 2.5 days later). One hundred and twenty nine women were included in this analysis accounting for 728 serum concentrations. The first sample was drawn 12 hours after administration and then every 24 hours; 265 concentrations were between LOD and LOQ; 60 women had an endogenous LH above LOQ at time zero. All analyses were performed with the software NONMEM version IV. A one-compartment model with first-order rate-limiting absorption was fitted to the data with an elimination rate constant fixed to 0.32 h-1(from IV data in healthy subjects) and a decreasing exponential model for the baseline (estimated from a control group, who did not received r-hLH). A specific error measurement model was set for concentrations between LOD and LOQ. Apparent volume of distribution was found to increase with dose. This nonlinearity was best described by a hyperbolic model for the relative bioavailability. Threefold and sixfold increase of dose led respectively to 20% and 34% decrease in relative bioavailability. Interindividual variability (IIV) for this parameter was negligible. For V at 5000 IU and absorption rate constant, mean (CV) were 18 L (37%) and 0.04 h-1 (16%). Covariates inclusion (body weight for both parameters and transaminase for volume only) decreased IIV to 35% and 12%. Such results will be used for subsequent pharmacodynamic analyses.
Reference: PAGE 7 (1998) Abstr 285 [www.page-meeting.org/?abstract=285]
Poster: poster