Pharmacokinetics and Pharmacodynamics of Follicle-Stimulating Hormone in Healthy Women Receiving Single and Multiple Doses of Highly Purified Human Menotrophin and Urofollitrophin

Background and Objective Highly purified human menotrophin and urofollitrophin preparations obtained from human urine via a novel patented purification method have been tested over a timeframe of 14 years in the studies presented in this article. The objective of the studies was to investigate the pharmacokinetics and the pharmacodynamics of follicle-stimulating hormone (FSH) after single subcutaneous and intramuscular doses and multiple subcutaneous doses of the tested preparations in healthy fertile pituitary-suppressed women. Designs We performed five open, randomised, crossover, single-dose bioequivalence and/or bioavailability studies and one open, multiple-dose, pharmacokinetics and pharmacodynamics study. Study Subjects and Treatments The six studies included 121 healthy fertile women taking their usual combined oral contraceptives for 3 months before the study: Study 1: 300 international units (IU) of highly purified menotrophin as single subcutaneous and intramuscular doses. Study 2: 300 IU of highly purified menotrophin (test formulation vs. comparator) as single subcutaneous doses. Study 3: 300 IU of highly purified urofollitrophin (hp-FSH) (test formulation vs. comparator) as single subcutaneous doses. Study 4: 300 IU (2 × 150 IU vs. 4 × 75 IU) of hp-FSH as single subcutaneous doses. Study 5: 225 and 445 IU of hp-FSH as single subcutaneous doses. Study 6: daily 225 IU of hp-FSH as subcutaneous doses for 5 consecutive days. Main Outcome Measures The main outcome measures were the FSH pharmacokinetic parameters, estradiol concentrations, and the number and size of the follicles. Results FSH after single subcutaneous and intramuscular injections of menotrophin or urofollitrophin attained a systemic peak (maximum) concentration ( C max ) that was on average consistent throughout the first four studies and ranged from 4.98 to 7.50 IU/L. The area under the plasma concentration–time curve (AUC) from administration to the last observed concentration time t (AUC t ) ranged from 409.71 to 486.16 IU/L·h and the elimination half-life ( t ½ ) ranged from 39.02 to 53.63 h. After multiple doses of urofollitrophin (225 IU) for 5 days, FSH attained a mean C max of 14.93 ± 2.92 IU/L and had an AUC during the time interval τ between two consecutive doses at steady state (AUC τ ) of 322.59 ± 57.92 IU/L·h, which was similar to the mean AUC t after a single subcutaneous dose of 225 IU of urofollitrophin in study 5 (306.82 ± 68.37 IU/L·h). Conclusions In our studies, the intramuscular and subcutaneous routes of menotrophin were equivalent; both menotrophin and urofollitrophin were bioequivalent to their marketed reference; FSH kinetic parameters following injection of urofollitrophin were dose proportional and independent from the administered concentration; and multiple doses of FSH increased estradiol levels and enhanced growth of follicles with a good dose–response correlation. Local tolerability was excellent throughout the six studies.