Follitropin delta

The most important effect resulting from parenteral administration of FSH is the development of multiple mature follicles.

Follitropin delta is a recombinant human FSH. The amino acid sequences of the two FSH subunits in follitropin delta are identical to the endogenous human FSH sequences. Because follitropin delta is produced in the human cell line PER.C6, the glycosylation profile is different from follitropin alfa and follitropin beta.

Pharmacodynamic effects

Following daily administration of equal IU doses of follitropin delta and follitropin alfa as determined in the rat in vivo bioassay (Steelman-Pohley assay), higher ovarian response (i.e. estradiol, inhibin B and follicular volume) was observed in patients after administration of follitropin delta compared to follitropin alfa. As the rat bioassay might not fully reflect the potency of the FSH in follitropin delta in humans, follitropin delta is dosed in micrograms and not in IU.

The number of oocytes retrieved increases with the dose of follitropin delta and serum AMH concentration. Conversely, increasing body weight leads to a decrease in the number of oocytes retrieved (only clinically relevant for follitropin delta doses below 12 micrograms).

The pharmacokinetic profile of follitropin delta has been investigated in healthy female subjects and in IVF/ICSI patients undergoing COS. Following repeated daily subcutaneous administrations, follitropin delta reaches steady-state within 6 to 7 days with a threefold higher concentration compared with the concentration after the first dose. Circulating levels of follitropin delta are inversely related to the body weight, which supports individualised dosing based on body weight. Follitropin delta leads to greater exposure than follitropin alfa.

Absorption

After daily subcutaneous administration of follitropin delta, the time to maximum serum concentration is 10 hours. The absolute bioavailability is about 64%.

Distribution

The apparent volume of distribution is about 25 L after subcutaneous administration and the volume of distribution at steady state is 9 L after intravenous administration. Within the therapeutic dose range, exposure to follitropin delta increases proportionally with the dose.

Elimination

Following subcutaneous administration, the apparent clearance of follitropin delta is 0.6 L/h and the clearance after intravenous is 0.3 L/h. The terminal elimination half-life after single subcutaneous administration is 40 hours and after multiple subcutaneous administration is 28 hours. The apparent clearance for follitropin delta is low, i.e. 0.6 L/h after multiple subcutaneous administration, leading to high exposure. Follitropin delta is expected to be eliminated similarly to other follitropins, i.e. mainly by the kidneys. The fraction of follitropin delta excreted unchanged in the urine was estimated to 9%.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and local tolerance. The overdose of follitropin delta resulted in pharmacological or exaggerated pharmacological actions. Follitropin delta had a negative effect on fertility and early embryonic development in rats when administered in doses ≥0.8 micrograms/kg/day which is above the recommended maximal dose in humans. The relevance of these findings for the clinical use of follitropin delta is limited.