Pharmacokinetics of recombinant human follicle stimulating hormone after intravenous, intramuscular, and subcutaneous administration in monkeys, and comparison with intravenous administration of urinary follicle stimulating hormone
Porchet, H.C.; Le Cotonnec, J.Y.; Canali, S.; Zanolo, G.
Drug Metabolism and Disposition the Biological Fate of Chemicals 21(1): 144-150
1993
ISSN/ISBN: 0090-9556 PMID: 8095209 Document Number: 408135
Recombinant human follicle stimulating hormone (r-hFSH; Gonal-F) is a new human FSH produced by a genetically engineered mammalian cell line (Chinese Hamster Ovary cells). To assess and compare its pharmacokinetics with urofollitropin (u-hFSH; Metrodin), extracted from the urine of postmenopausal women, we performed a cross-over study in 12 monkeys. The received 10 IU/kg iv of u-hFSH and r-hFSH. Then all received a single 10 IU/kg dose im and sc of r-hFSH. In the third phase, six monkeys received 10 IU/kg/day im of r-hFSH for 7 days when the six others received the same regimen subcutaneously. Blood was withdrawn at predetermined time points, and FSH serum concentrations were measured by an immunoenzymetric assay. Data were analyzed individually by fitting a two-compartment pharmacokinetic model for the intravenous routes and a one-compartment first-order absorption model for the intramuscular and subcutaneous routes. After intravenous administration of u-hFSH and r-hFSH, mean FSH concentration-time curves were almost parallel. AUC-O infin was significantly smaller after r-hFSH (846 IU cntdot hr-1/liter +- 125) than after a-h FSH 1377 IU cntdot hr-1/liter +- 236) (p lt 0.005; analysis of variance), because the u-hFSH immunological dose was greater (8.77 IU/kg) than the r-hFSH immunological dose (6.94 IU/kg). Thus total clearance for r-hFSH (0.008 liter/hr/kg +- 0.001) and for u-hFSH (0.007 liter/hr/kg +- 0.001) was almost similar. Distribution half-lives (1.5 hr +- 0.1 and 1.8 hr +- 0.4) and terminal half-lives (15.3 hr +- 3.8 and 15.5 hr +- 5.1) for r-hFSH and u-hFSH were similar. After single intramuscular and subcutaneous r-hFSH administration, mean concentration-time curves were superimposable except for the C-max that was higher (23.5 IU/liter +- 10.5) after intramuscular than after subcutaneous injection (15.5 IU/liter +- 6.6) (p lt 0.005). Absorption half-life tended to be shorter after intramuscular (1.7 hr +- 0.7) than subcutaneous injection (3.4 hr +- 1.7), but terminal half-lives were comparable (19.2 hr +- 5.7 and 20.7 hr +- 3.4) as absolute bioavailability (77% +- 24 and 71% +- 28). Repeated administration confirmed these results. Steady-state was reached after 2 to 3 days, with an accumulation factor of 2 between first and last doses with both routes. r-hFSH is pharmacokinetically equivalent to u-hFSH. After both intramuscular and subcutaneous single and repeated daily administrations, the pharmacokinetics of r-hFSH is similar.