Daniël Jonker (1), Lars Erichsen (2), Bjarke Mirner Klein (1) and Joan-Carles Arce (1)
(1) Ferring Pharmaceuticals A/S, Copenhagen, Denmark (2) Currently Novo Nordisk A/S, Søborg, Denmark
Introduction: Follitropin delta is a novel recombinant follicle-stimulating hormone (FSH) preparation produced by a human cell line. It has been developed for controlled ovarian stimulation in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Setting the starting dose of FSH is challenged by the fact that the ovarian response varies greatly across patients given the same starting dose of FSH, and that a too high response increases the risk of ovarian hyperstimulation syndrome, which is a potentially life-threatening condition.
Objective: To establish an individualized dosing regimen for follitropin delta resulting in a more appropriate ovarian response.
Methods: The relationship between the dose of follitropin delta and the number of oocytes retrieved was studied in 222 IVF/ICSI patients randomized to daily doses of 5.2, 6.9, 8.6, 10.3 or 12.1 μg follitropin delta [1]. Randomization was stratified by serum anti-Müllerian hormone (AMH) level at screening. The number of oocytes retrieved (OR) was used as a marker for ovarian response and the dose-response relationship was described using a negative binomial model [2] implemented in NONMEM. A stepwise covariate selection procedure was applied to identify predictive factors for OR, such as the AMH level.
Results: A sigmoid Emax dose-response relation was found to describe the data adequately with weight-adjusted dose (µg/kg) being a better predictor than unadjusted dose (µg). Among five evaluated covariates, baseline AMH level explained most of the variability in OR and was the only covariate retained. The model was used to estimate, for a range of AMH levels, the dose of follitropin delta required to achieve an appropriate ovarian response. This resulted in the following proposal: a fixed daily dose decreasing from 0.19 to 0.10 µg/kg body weight by increasing AMH (maximum daily dose 12 µg) in patients with AMH ≥15 pmol/L and a fixed daily dose of 12 µg in patients with AMH < 15 pmol/L. The proposed dosing regimen was subsequently evaluated in a confirmatory Phase 3 study and resulted in the expected reduction of the number of patients with extreme ovarian response.
Conclusions: Follitropin delta is the first human recombinant FSH developed to offer women precise dosing according to their AMH levels and body weight. This dosing regimen is a new paradigm in fertility management and was established using dose-response modelling.
References:
[1] Arce J-C, Nyboe Andersen A, Fernández-Sánchez M, et al. Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone-stratified, dose-response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 2014, 102:1633-1640.
[2] Troconiz IF, Plan EL, Miller R and Karlsson M. Modelling overdispersion and markovian features in count data. J. Pharmacokinet Pharmacodyn 2009, 36:461-477.
Reference: PAGE 25 (2016) Abstr 5997 [www.page-meeting.org/?abstract=5997]
Poster: Drug/Disease modeling - Endocrine