Abarelix, sold under the brand name Plenaxis, is a synthetic decapeptide and Gonadotropin-releasing hormone (GnRH) antagonist which are a class of medications that inhibit the hormone from binding to its receptor, and can induce a pharmacological hypophysectomy. GnRH antagonists compete with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body. Abarelix is composed of ten natural and non-natural amino acid residues in a linear sequence and is developed for the treatment of prostate cancer.
Testosterone promotes growth of many prostate tumors and therefore reducing circulating testosterone to very low (castration) level is often the treatment goal in the management of men with advanced prostate cancer. Abarelix works by reducing the amount of testosterone, and it directly and competitively binds to and blocks the gonadotropin releasing hormone receptor in the anterior pituitary gland, thereby inhibiting the secretion and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). However, due to the direct inhibition of the secretion of LH, it does not initially increase the level of serum testosterone. It is primarily used in oncology to reduce the amount of testosterone in patients with advanced symptomatic prostate cancer for which no other treatment options are available.
Unlike currently available luteinizing hormone-releasing hormone (LHRH) agonists, abarelix does not induce an initial surge of testosterone, LH, dihydrotestosterone (DHT), or FSH, which is an important finding because prostate cancer is influenced by several hormones. In Phase 1-2 studies, abarelix rapidly and significantly reduced testosterone, FSH, LH, DHT, and prostate-specific antigen (PSA) levels in men with prostate cancer. The exposure of the prostate cancer cells to these hormones, which may enhance cellular proliferation, is substantially less with abarelix than with other currently available drugs. A randomized, multi-institutional Phase 3 study comparing abarelix with leuprolide acetate further evaluated the efficacy and safety of abarelix in the management of prostate cancer.
Pharmacokinetics and metabolism
Abarelix has high water solubility and it has been evaluated in subcutaneous continuous injection and in depot formulation. Abarelix binds highly to plasma proteins. Metabolism studies were conducted in vitro in rat, monkey and human hepatocytes and in vivo in rats and monkeys. These studies showed that major metabolites of abarelix are formed via the hydrolysis of peptide bonds and that there are no significant oxidative or conjugated metabolites. There is no evidence for the implication of cytochrome P450. Abarelix is excreted in the urine at a 13% rate after administration of 15 μg/kg i.m. with no metabolite.
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