The population pharmacokinetics of recombinant- and urinary-human follicle stimulating hormone in women.

AIMS

To characterize the pharmacokinetics of recombinant-human follicle stimulating hormone (r-hFSH) and urinary-human follicle stimulating hormone (u-hFSH) using population pharmacokinetic analysis and deconvolution techniques.

METHODS

Sparse data were available from 62 female patients who received u-hFSH intramuscularly (i.m.) and 60 female patients who received r-hFSH subcutaneously (s.c.) as part of an in vitro fertilisation and embryo transfer (IVF-ET) procedure. The dose of u-hFSH 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 depended upon the ovarian response. Intensively sampled data were also available from 12 female volunteers who received r-hFSH, 150 IU, on three occasions: intravenously (i.v.), i.m. and s.c., each separated by 1 week of wash-out. The volunteers then received multiple r-hFSH doses by the 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 IU, 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 compounds. The population estimate of clearance (CL) after i.v. administration was 0.60 and 0.44 l h(-1) for r-hFSH and u-hFSH respectively. The calculated mean residence times (MRT) for r-hFSH and u-hFSH were 16 and 18 h, respectively. The different bioavailabilities (F) and mean absorption times (MAT) determined after i.m. and s.c. administration ranged from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, administration route, data type and method of analysis. Population analysis 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 l h(-1) for r-hFSH and u-hFSH respectively. Urinary-hFSH CL/F increased linearly with weight and was 0.33 l h(-1) at the average weight of 58.5 kg. No other covariates (age, weight, height, creatinine clearance, body mass index, race) were found to influence the FSH disposition parameters. The sparse data population estimates of intersubject variability in 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.