Clinical pharmacology of recombinant human follicle-stimulating hormone. III. 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.


METHODS
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 E2 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 E2 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 E2 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 E2, indicating that inhibin serum levels are tracking FSH concentrations more closely than E2 serum levels.


CONCLUSIONS
[1] Recombinant human FSH alone is effective to stimulate ovarian follicular development and steroidogenesis in women pretreated with a GnRH agonist despite complete LH suppression; [2] there is a large interindividual variability in the response to recombinant human FSH; [3] this variability is mainly related to ovarian sensitivity to FSH rather than difference in pharmacokinetics; [4] inhibin is an early index of follicular development, further supporting its role as a putative tool to monitor FSH therapy; and [5] a slow stepwise increase in FSH dose is recommended if FSH overexposure and excessive ovarian stimulation are to be minimized. These observations suggest that recombinant human FSH will in the near future replace urinary human FSH in the clinics.
Porchet
H C
HC
Ares Serono, Geneva, Switzerland.
le Cotonnec
J Y
JY
Loumaye
E
E
D000328:Adult; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007265:Inhibins / Q000097:blood; D007700:Kinetics; D008954:Models, Biological; D006080:Ovarian Follicle / Q000033:anatomy & histology / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
D011994:Recombinant Proteins; D004958:Estradiol; D007265:Inhibins; D005640:Follicle Stimulating Hormone