P-576 Pharmacokinetic and pharmacodynamic modelling to explore dosing regimens of corifollitropin alfa for ovarian stimulation without the need for additional daily recFSH injections
Authors: Fatemi H  M , Polyzos N , Larsson P , Mannaerts B 
Published: July 2024

Abstract

Study question
Can ovarian stimulation in IVF patients be realized with one or two corifollitropin alfa (CFA) injections only?

Summary answer
For 94% of IVF patients, ovarian stimulation can be safely completed with a maximum of two CFA injections

What is known already
A single dose CFA replaces the first week of stimulation with daily recFSH, providing ovarian stimulation similar to daily 300 IU recFSH. Pharmacokinetic and pharmacodynamic (PK/PD) modelling has shown that a threshold serum FSH concentration of 1.1 ng/ml (∼ 6.72 IU/L) is required to maintain multiple follicular development, and that such FSH concentrations are maintained for 7 days following single injection. From day 8 onwards, most patients require daily recFSH injections to maintain serum FSH above threshold to complete the follicular growth. Patients requiring profound stimulation, e.g. prior to ‘freeze-all’, would benefit most from CFA only treatment, requiring less injections.

Study design, size, duration
This was a retrospective analysis using individual patient data from 4 large CFA trials, including totally 2397 IVF patients receiving a single injection of CFA followed by daily follitropin beta injections from day 8 of stimulation until triggering.

Participants/materials, setting, methods
A PK model developed for CFA was used to predict serum concentrations following different dosing regimens of CFA only. Clinical trial data from 2397 patients was used to estimate the distribution of the required length of stimulation and to evaluate the impact of different dosing regimens on the serum FSH concentrations up to the day of triggering.

Main results and the role of chance
At stimulation day 8, 21% of patients did not require additional FSH, whereas 25%, 27%, 14%, and 7% needed 1, 2, 3 or 4 days additional stimulation days to complete the cycle. Only 6% required more than 4 days additional stimulation. Patients below 60 kg remained longer above the threshold and additional dosing could have been delayed to stimulation day 9-11 depending on the initial dose (100 or 150 mg). In a 70 kg woman, daily doses of 7 mg CFA would be sufficient to maintain trough concentrations of FSH above the threshold, and a single dose of 15 and 30 mg on day 8 would sustain stimulation for another 2 and 4 days, respectively. A single dose of 30 mg on day 8 would increase FSH concentrations from 7 IU/L to a maximal level of approximately 12 IU/L, a fluctuation that is unlikely to recruit new small follicles during the late follicular phase. It is therefore suggested that patients can be safely treated with a second dose of 30 mg CFA on day 8 of stimulation, without risk of overdosing when receiving GnRH agonist triggering, and that 94% of patients will not need more than two doses.

Limitations, reasons for caution
The theoretical dosing regimens build upon this retrospective analysis and modelling needs to be validated in a clinical study to confirm that one additional dose of CFA is able to complete ovarian stimulation efficiently.

Wider implications of the findings
IVF patients planned to have ‘freeze-all’ following GnRH agonist triggering may be treated conveniently with one or max two injections of CFA for ovarian stimulation.

Trial registration number
not applicable