Luveris (INN lutropin alfa)

Luveris (INN lutropin alfa) is a sterile lyophilized powder composed of recombinant human luteinizing hormone, r-hLH. r-hLH is a heterodimeric glycoprotein consisting of two non-covalently linked subunits (designated α and β) of 92 and 121 amino acids, respectively. The carbohydrate chain attachment to the r-hLH protein core occurs via N- but not O-linkage. The N-glycosylation sites are Asn-52 and Asn-78 for the α–subunit and Asn-30 for the β–subunit. The β-chain has an N-glycosylation site and its structure and glycosylation pattern are very similar to that of pituitary-derived hLH. The production process involves expansion of genetically modified Chinese Hamster Ovary (CHO) cells from an extensively characterized cell bank into large scale cell culture processing.

Lutropin alfa is secreted by the CHO cells directly into the cell culture medium that is then purified using a series of chromatographic steps. The biological activity of lutropin alfa is determined using the Van Hell Bioassay described in the British Pharmacopoeia. The in vivo biological activity is determined using a house standard properly calibrated against the relevant international standard.

Luveris is a sterile, lyophilized powder, which after reconstitution with Sterile Water for Injection, USP, is intended for subcutaneous (sc) administration. Each vial of Luveris® contains 82.5 IU lutropin alfa, 48 mg sucrose, 0.83 mg dibasic sodium phosphate dihydrate, 0.052 mg monobasic sodium phosphate monohydrate, 0.05 mg polysorbate 20, and 0.1 mg L-methionine. Phosphoric acid and/or sodium hydroxide are used to adjust the pH. After reconstitution with 1 mL of enclosed diluent, the product will deliver 75 IU of recombinant human lutropin alfa. The pH of the reconstituted solution is 7.5 to 8.5.

The physicochemical, immunological, and biological activities of Luveris are comparable to those of human pituitary LH. In the ovaries, during the follicular phase, LH stimulates theca cells to secrete androgens, which will be used as the substrate by granulosa cell aromatase enzyme to produce estradiol, supporting Follicle-Stimulating Hormone (FSH)-induced follicular development. Luveris® is administered concomitantly with Gonal-f® (follitropin alfa for injection) to stimulate development of a potentially competent follicle and to indirectly prepare the reproductive tract for implantation and pregnancy.

Pharmacokinetics
When given by intravenous administration, Luveris demonstrates linear pharmacokinetics over the 300 to 40,000 IU dose range. Following a 75 IU dose, the concentration range is too small to allow proper quantification of the pharmacokinetic parameters. The disposition of r-hLH is adequately described by a biexponential model. Following subcutaneous administration, the terminal half-life is slightly longer than after intravenous administration. Upon repeated daily administration, a modest accumulation takes place (accumulation ratio of 1.6 ± 0.8).

Absorption
Following subcutaneous administration of Luveris®, maximum serum concentration is reached after approximately 4 to 16 hours.

The mean absolute bioavailability of Luveris® following a single subcutaneous injection (at a much higher dose to allow proper quantification, i.e. 10,000 IU) to healthy female volunteers is 56 ± 23%, supported by an immunoassay method. There were no statistical differences between the intramuscular and subcutaneous routes of administration for Cmax, tmax, or bioavailability.

Distribution
Following an intravenous dose of 300 IU of Luveris®, a rapid distribution phase (t½λ1 of approximately 1 hour) and a terminal half-life (t½) of approximately 11 hours were observed for r-hLH. The steady state volume of distribution (Vss) was approximately 10 L. Mean residence time (MRT) was approximately 6 hours.

Metabolism/Excretion
Following subcutaneous administration of Luveris®, r-hLH is eliminated from the body with a mean terminal half-life of about 18 hours. Total body clearance is approximately 2 to 3 L/h with less than 5 percent of the dose being excreted unchanged renally.

Pharmacodynamics
In the stimulation of follicular development, the primary effect resulting from administration of Luveris® is an increase in estradiol secretion by the follicles, the growth of which is stimulated by FSH.

Special populations
Pharmacokinetics of Luveris® in the geriatric or pediatric populations or in patients with renal or hepatic insufficiency have not been established.

Drug-Drug Interactions
There are no pharmacokinetic interactions with Gonal-f® (follitropin alfa for injection) when administered simultaneously. No drug-drug interaction studies have been conducted.

Project manager:
Elena Shoina
+7 495 921-25-15
e.shoina@medintorg.ru

www.medintorg.ru