Corifollitropin alfa

Corifollitropin alfa is designed as a sustained follicle stimulant with the same pharmacodynamic profile as (rec)FSH, but with a markedly prolonged duration of FSH activity. The long duration of FSH activity was achieved by adding the carboxy-terminal peptide of the β-subunit of human chorionic gonadotropin (hCG) to the β-chain of human FSH. Corifollitropin alfa does not display any intrinsic LH/hCG activity.

In females

Due to corifollitropin alfa’s ability to initiate and sustain multiple follicular growth for an entire week, a single subcutaneous injection of the recommended dose may replace the first seven injections of any daily (rec)FSH preparation in a COS treatment cycle.

Paediatric adolescent male population (14 years and older)

Corifollitropin alfa’s sustained FSH activity stimulates the immature Sertoli cells in the testis to initiate gonadal development in support of future spermatogenesis. The combination of FSH with hCG is to initiate puberty with stimulation of Leydig cell function and increase testosterone production until testicular volumes attain adult size.

Pharmacokinetic parameters of corifollitropin alfa were evaluated after subcutaneous administration in women undergoing a COS treatment cycle.

Due to the long elimination half-life, after administration of the recommended dose, serum concentrations of corifollitropin alfa are sufficient to sustain multiple follicular growth for an entire week. This justifies replacement of the first seven injections of daily (rec)FSH with a single subcutaneous injection of corifollitropin alfa in COS for the development of multiple follicles and pregnancy in an ART program.

Body weight is a determinant of exposure to corifollitropin alfa. Corifollitropin alfa exposure after a single subcutaneous injection is 665 hours*ng/mL (AUC, 426-1,037 hours*ng/mL¹) and is similar after administration of 100 micrograms corifollitropin alfa to women with a body weight less than or equal to 60 kilograms and of 150 micrograms corifollitropin alfa to women with a body weight greater than 60 kilograms.

Absorption

After a single subcutaneous injection of corifollitropin alfa, the maximum serum concentration of corifollitropin alfa is 4.24 ng/mL (2.49-7.21 ng/mL¹) and is reached 44 hours (35-57 hours¹) postdose. The absolute bioavailability is 58% (48-70%¹).

Distribution

Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady state volume of distribution is 9.2 L (6.5-13.1 L¹). Exposure to corifollitropin alfa increases proportionally with dose within the range of 60 micrograms to 240 micrograms.

Elimination

Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours¹) and a clearance of 0.13 L/h (0.10-0.18 L/h¹). Elimination of corifollitropin alfa predominantly occurs via the kidneys, and the rate of elimination may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa.

¹ Predicted range for 90% of subjects.

Other special populations

Hepatic impairment

Although data in hepatically impaired patients are not available, hepatic impairment is unlikely to affect the pharmacokinetic profile of corifollitropin alfa.

Paediatric population

In a study of adolescent males 14 to less than 18 years of age with hypogonadotropic hypogonadism (n=17) who were administered 100 micrograms (body weight less than or equal to 60 kg) or 150 micrograms (body weight greater than 60 kg) of corifollitropin alfa once every two weeks, mean serum trough corifollitropin alfa concentrations (two weeks postdose) were 591 ng/mL when corifollitropin alfa was administered alone and 600 ng/mL when corifollitropin alfa was co-administered with hCG (given twice weekly). Corifollitropin alfa serum concentrations were comparable in participants receiving 100 micrograms and 150 micrograms doses of corifollitropin alfa.

Preclinical data revealed no special hazard for humans based on conventional studies of single and repeated dose toxicity and safety pharmacology.

Reproduction toxicology studies in rats and rabbits indicated that corifollitropin alfa does not adversely affect fertility. Administration of corifollitropin alfa to rats and rabbits, prior to and directly after mating, and during early pregnancy, resulted in embryotoxicity. In rabbits, when administered prior to mating, teratogenicity has been observed. Both embryotoxicity and teratogenicity are considered a consequence of the superovulatory state of the animal not able to support a number of embryos above a physiological ceiling. The relevance of these findings for the clinical use of Elonva is limited.