Abstract
Study question
Which individual subject characteristics affect systemic FSH concentrations in women undergoing controlled ovarian stimulation with follitropin delta?
Summary answer
Body weight is the main determinant of systemic FSH concentrations. Renal function, Asian race, country/region, hepatic function and age have at most a small influence.
What is known already
After administration of FSH, systemic FSH concentrations are inversely related to body weight. It has been observed that the impact of body weight on ovarian response is clinically relevant at low doses but not at high doses. In patients with anti-Müllerian hormone (AMH) ≥15 pmol/L, follitropin delta is dosed according to each patient’s body weight, which influences systemic FSH concentrations, and her AMH level which predicts ovarian response.
Study design, size, duration
Serum FSH concentrations were assessed in five randomised, controlled, assessor-blinded, multicentre trials of follitropin delta in women undergoing an assisted reproductive technology programme. The trials were conducted in Europe, America and Asia. In all, 1.665 women treated with follitropin delta contributed to the evaluation with 4052 serum FSH concentrations, measured at steady state by an immunoassay.
Participants/materials, setting, methods
FSH concentrations were described with a pre-specified one-compartment population pharmacokinetic model. The key model parameters were the apparent total clearance (CL/F) of follitropin delta, the interindividual variability herein and the effects of baseline values of body weight, age, race, country/region, renal and hepatic function on CL/F. Renal function was assessed using the estimated glomerular filtration rate (eGFR) and hepatic function by alanine transaminase (ALT) and bilirubin levels.
Main results and the role of chance
The area under the FSH concentration-time curve during a dosing interval (AUC) was derived from dose and CL/F. Body weight was the covariate with the most pronounced effect on AUC, both in terms of the effect magnitude and statistical significance. AUC was 1.51-fold higher (90% confidence limits: 1.48; 1.54) in women with the lowest observed body weight of 40 kg compared to women with a typical body weight of 58 kg. The effect of renal function on AUC was small and in the same order of magnitude as the bioequivalence limits (0.8; 1.25). AUC was 1.28-fold higher (90% confidence limits: 1.23; 1.33) in women with the lowest observed eGFR value of 44 mL/min/1.73m2, compared to women with a typical eGFR value of 98 mL/min/1.73m2. The effects of Asian race and country/region (Japan, China, Other Asian) were confounded with each other and well within the bioequivalence limits when evaluated independently. The effects of age and the hepatic function markers ALT and bilirubin were well within the bioequivalence limits.
Limitations, reasons for caution
The women participating in the trials were generally healthy and the results cannot be transferred to women with renal or hepatic disease. A limited number of Black women contributed to the present analysis but the trend was similar. Data is forthcoming from ongoing trials including larger numbers of Black women.
Wider implications of the findings: The findings support dosing follitropin delta by body weight and without adjustment for renal function, hepatic function, race, age or country/region.
Trial registration number
NCT01426386, NCT02309671, NCT01956110, NCT03228680 and NCT03296527
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