THE POPULATION PHARMACOKINETICS OF RECOMBINANT-HUMAN AND URINARY-HUMAN FOLLICLE-STIMULATING-HORMONE IN WOMEN

Aims To characterize the pharmacokinetics of recombinant-human follicl e stimulating hormone (r-hFSH) and urinary-human follicle stimulating hormone (u-hFSH) using population pharmacokinetic analysis and deconvo lution techniques, Methods Sparse data were available from 62 female p atients who received u-hFSH intramuscularly (i.m.) and 60 female patie nts who received r-hFSH subcutaneously (s.c.) as part of an ii? vitro fertilisation and embryo transfer(IVF-ET) procedure. The dose of u-hFS H and r-hFSH was 225 International Units (IU) FSH/day for the first 5 days of treatment. The dose of u-hFSH/r-hFSH on subsequent days depend ed upon the ovarian response. Intensively sampled data were also avail able from 12 female volunteers who received r-hFSH, 150 IU, on three o ccasions: intravenously (i.v.), i.m. and s.c., each separated by 1 wee k of wash-out. The volunteers then received multiple r-hFSH doses by t he s.c. route: 150 IU once daily for 7 days, Intensively sampled data were available from a further 12 female volunteers who received u-hFSH , 150 TCT, given by the i.v. and i.m. routes. Results Analysis of the intensively sampled r-hFSH and u-hFSH data sets found that disposition could be described using a two-compartment model and that absorption was rate limiting and essentially a first order process, for both comp ounds. The population estimate of clearance (CU) after i.v. administra tion was 0.60 and 0.44 lh(-1) for r-hFSH and u-hFSH respectively. The calculated mean residence times (MRT) for r-hFSH and u-hFSH were 16 an d 18 h, respectively, The different bioavailabilities (F) and mean abs orption times (MAT) determined after i.m. and s.c. administration rang ed from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, adm inistration route, data type and method of analysis. Population analys is of the sparse patient data found that a one compartment model with first order absorption was adequate to describe the r-hFSH and u-hFSH data. The population estimates of apparent clearance (CL/F) were 0.71 and 0.33 lh(-1) for r-hFSH and u-hFSH respectively. Urinary-hFSH CL/F increased linearly with weight and was 0.33 Ih at the average weight o f 58.5 kg. No other covariates (age, weight, height, creatinine cleara nce, body mass index, race) were found to influence the FSH dispositio n parameters. The sparse data population estimates of intersubject var iability ill CL/F for r-hFSH and u-hFSH were essentially the same, 26% and 25%, respectively. Conclusions The population analysis indicates that the variability in CL/F is moderate, consequently so would be the variability in exposure, given a fixed dosage regimen.