Lutropin alfa is a recombinant human Luteinising Hormone (r-hLH), a glycoprotein composed of noncovalently bound α- and ß-subunits. Luteinising Hormone (LH) binds on the ovarian theca (and granulosa) cells and testicular Leydig cells, to a receptor shared with human chorionic gonadotropin hormone (hCG). This LH/CG transmembrane receptor is a member of the super-family of G proteincoupled receptors; specifically, it has a large extra-cellular domain.
In vitro the affinity binding of recombinant hLH to the LH/CG receptor on Leydig tumour cells (MA-10) is between that for hCG and that of pituitary hLH, but within the same order of magnitude.
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 FSH-induced follicular development. At mid-cycle, high levels of LH trigger corpus luteum formation and ovulation. After ovulation, LH stimulates progesterone production in the corpus luteum by increasing the conversion of cholesterol to pregnenolone.
In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of lutropin alfa is an increase in estradiol secretion by the follicles, the growth of which is stimulated by FSH.
The pharmacokinetics of lutropin alfa have been studied in pituitary desensitised female volunteers from 75 IU up to 40,000 IU. The pharmacokinetic profile of lutropin alfa is similar to that of urinaryderived hLH.
Following subcutaneous administration, the absolute bioavailability is approximately 60%.
Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of approximately one hour. The steady state volume of distribution is around 10-14 l. The mean residence time is approximately 5 hours.
Lutropin alfa shows linear pharmacokinetics, as assessed by area under curve (AUC) which is directly proportional to the dose administered. The lutropin alfa pharmacokinetics following single and repeated administration are comparable and the accumulation ratio of lutropin alfa is minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.
Following subcutaneous administration, lutropin alfa is eliminated from the body with a terminal half-life of about 10-12 hours. Following subcutaneous administration, the terminal half-life is slightly prolonged. Total body clearance is around 2 l/h with less than 5% of the dose being excreted in the urine.
Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. As expected from the heterologous protein nature of the hormone, lutropin alfa raised an antibody response in experimental animals after a period that reduced the measurable serum LH levels but did not fully prevent its biological action. No signs of toxicity due to the development of antibodies to lutropin alfa were observed.
At doses of 10 IU/kg/day and greater, repeated administration of lutropin alfa to pregnant rats and rabbits caused impairment of reproductive function including resorption of foetuses and reduced body weight gain of the dams. However, drug-related teratogenesis was not observed in either animal model.
Other studies have shown that lutropin alfa is not mutagenic.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
