CLINICAL-PHARMACOLOGY OF RECOMBINANT HUMAN FOLLICLE-STIMULATING-HORMONE .3. PHARMACOKINETIC-PHARMACODYNAMIC MODELING AFTER REPEATED SUBCUTANEOUS ADMINISTRATION

Objective: To investigate the respective role of the pharmacokinetic and of the pharmacodynamic characteristics in individual variability and to reassess the time course and the informative value of FSH pharmacodynamic markers by applying a combined pharmacokinetic-pharmacodynamic modeling analysis. Design: After a 1-week SC administration of 150 IU/d of recombinant human FSH (Gonal-F; Laboratoires Serono, Aubonne, Switzerland) to 12 healthy down-regulated female volunteers, inhibin and E(2) serum level and total follicular volume were recorded at preset times during 2 weeks. Results: Good correlations were obtained between inhibin maximal levels and maximal total follicular volumes and between E(2) maximal serum level increases and maximal total follicular volumes. In contrast, no correlation was found between maximal serum concentration of FSH and any of the recorded effects. Pharmacodynamic effects started to increase significantly later than FSH serum concentration, especially for E(2) serum level and total follicular volume. Inhibin serum level was the first pharmacodynamic marker to increase. A full pharmacokinetic-pharmacodynamic model was developed to determine the relationship between drug concentrations and FSH pharmacological effects. This approach provides a better understanding of the concentration-effect relationship and should allow a rational design for recombinant human FSH dose regimen. The average equilibration half-life between serum concentrations and theoretical effect-compartment concentrations is approximately 2 days for inhibin and approximately 4 days for E(2), indicating that inhibin serum levels are tracking FSH concentrations more closely than E(2) serum levels.