O-013 Population pharmacokinetics of follitropin delta during ovarian stimulation

Abstract

Abstract Study question Which patient characteristics affect serum follicle stimulating hormone (FSH) concentrations in women undergoing ovarian stimulation (OS) with follitropin delta, a human cell line derived FSH? Summary answer Body weight is the main determinant of serum FSH concentrations during OS. Renal function, race, ethnicity, hepatic function and age have at most small influence. What is known already The pharmacokinetics of FSH have been studied in dedicated studies with serial blood sampling, typically conducted in healthy subjects. Such studies are designed to provide detailed pharmacokinetic profile information but lack the statistical power for identifying individual patient characteristics affecting FSH exposure. Population pharmacokinetic modelling enables evaluating the influence of patient characteristics based on few FSH measurements per patient if data from many patients are available. Study design, size, duration Serum FSH concentrations were assessed by immunoassay in seven randomized, controlled, blinded, multicentre trials of follitropin delta in women undergoing an assisted reproductive technology program. The trials were conducted in the United States, Canada, Europe, Brazil, and Asia. In all, 2,721 women treated with follitropin delta contributed to the evaluation with 6,952 FSH measurements. 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 in CL/F and the effects of baseline values of body weight, age, race, ethnicity, 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 Area under the FSH concentration-time curve during a dosing interval (AUC) was derived from dose and CL/F. Body weight had the most pronounced effect on AUC, both in terms of effect magnitude and statistical significance. AUC was 1.28-fold higher (90% confidence limits: 1.25; 1.30) in women with a body weight of 47 kg (5th percentile) compared to women with a median body weight of 62 kg. The effect estimates of eGFR, Asian race and Black race on CL/F were within the bioequivalence limits of 0.80 and 1.25, but with 90% confidence limits not including a value of 1. The effect of Black race was estimated to be a 1.19 fold (90% confidence limits: 1.12; 1.26) higher AUC, as compared to White race. Despite this, the individual estimates of AUC were close to identical comparing these patient populations (mean (SD) relative to a typical study participant: 1.00 (0.25) and 0.97 (0.23), respectively). This is likely due to the mean body weight being higher in Black trial participants compared to White trial participants (78.3 kg compared to 68.2 kg). The effects of age, ethnicity and the hepatic function markers ALT and bilirubin were well within the bioequivalence range of 0.80 – 1.25. Limitations, reasons for caution Potential effects of subject characteristics on PK parameters such as subcutaneous absorption rate or volume of distribution could not be evaluated due to the number of serum FSH concentration measurements available per patient. Wider implications of the findings After follitropin delta administration, serum FSH concentrations are inversely related to body weight; this may be helpful for determining whether there is a need to consider body weight when selecting dose. Trial registration number NCT01426386, NCT02309671, NCT01956110, NCT03228680, NCT03296527, NCT03740737, NCT03738618, NCT03809429