Corifollitropin Alfa

Uses

Corifollitropin Alfa is a FSH analogue indicated for Controlled Ovarian Stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program.

Controlled ovarian stimulation in cases of women who are undergoing fertility treatment to stimulate the development of more than one mature egg simultaneously in the ovaries in combination with a gonadotrophin-releasing hormone (GnRH) antagonist (a type of medicine also used in fertility treatments).

How Corifollitropin Alfa works

Corifollitropin Alfa is a long-lasting single injection fusion protein which lacks luteinizing hormone (LH) activity. Only one injection is needed for the first 7 days, which replaces the first 7 daily injections of traditional follicle stimulating hormone (FSH). It is a follicle-stimulation hormone (human α-subunit reduced), a combination of follicle stimulation hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit) . Frequent, repetitive injections increase stress and error rates, and are often a burden for women, leading to therapy noncompliance .

The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH .

Corifollitropin Alfa serves as a sustained follicle stimulant that has similar pharmacological effects to recombinant follicle stimulating hormone (rFSH), however, with a relatively long elimination half-life, resulting in a longer duration of action. This is achieved using site-directed mutagenesis and gene transfer techniques to create a glycoprotein that consists of an α-subunit that is identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit comprised of a complete β-chain of human FSH elongated by the carboxyterminal peptide of the β-subunit of human chorionic gonadotrophin (hCG) . This unit interacts with the FSH receptor to stimulate the release of oocytes.

Corifollitropin Alfa does not demonstrate any intrinsic LH/hCG activity .

Toxicity

The most common side effects with Elonva (seen in between 1 and 10 patients in 100) include a headache, nausea, fatigue, pelvic pain and/or discomfort, breast tenderness and ovarian hyperstimulation syndrome (OHSS). This syndrome occurs when the ovaries have a heightened response to therapy, leading to abdominal swelling and pain, nausea and diarrhea .

More than one injection of Elonva within one treatment cycle or an excessively high dose of Elonva and/or (rec)FSH can increase the risk of ovarian hyperstimulation syndrome , which may cause swollen or painful ovaries, abdominal bloating, nausea, and a weight gain of up to 3kg .

In severe cases, ovarian hyperstimulation syndrome may cause rapid weight gain ranging from 15 to 20 kilograms in 5-10 days. Severe abdominal pain, severe, persistent nausea, and vomiting, decreased urination, and abdominal bloating, as well as other generalized symptoms, may occur . About 1 - 2 % of women undergoing ovarian stimulation develop a severe form of ovarian hyperstimulation syndrome (OHSS). Severe OHSS can be life-threatening. Complications may include: ascites, pulmonary edema, electrolyte disturbances (sodium, potassium, others), thrombosis in large vessels, usually in the lower extremities, renal failure, ovarian torsion, rupture of ovarian cysts. Some of these conditions can lead to hemorrhage, respiratory failure, spontaneous miscarriage or pregnancy termination due to complications, resulting in death .

Food Interaction

Volume of 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 .

Exposure to corifollitropin alfa increases in a linear fashion with the dose within a range of 60 micrograms - 240 micrograms .

Elimination Route

After one single subcutaneous injection of this drug, the maximal serum concentration is 4.24 ng/mL (2.49-7.21 ng/mL1) and is reached 44 hours (35-57 h) post-dose administration. Its absolute bioavailability is 58% (48-70%) .

Half Life

Corifollitropin Alfa has a longer half-life compared with FSH and thus requires less frequent dosing .

Corifollitropin Alfa has an elimination half-life of 70 hours (59-82 hours) .

Clearance

0.13 L/h (0.10-0.18 L/h1)

Elimination Route

Radioactivity labeling showed that the drug was mainly (86%) excreted in the urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, but only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part) .

Elimination of corifollitropin alfa mainly occurs via the kidneys. The elimination rate of this drug may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa .

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