cetrorelix and abarelix

GnRH agonists have a proven and well-established role in the management of prostate cancer. Further adaptations of the amino-acid sequence led to the development of antagonists with potential therapeutic uses, including a possible role in prostate cancer patients. Treatment of prostate cancer with GnRH agonists results in an initial flare of symptoms that may be prevented by co-administration of a steroidal or non-steroidal antiandrogen. However, this can be associated with additional adverse effects. Clinical studies have shown that GnRH antagonists produce a rapid decline in testosterone but without the disease flare. However these short-term effects have yet to be proven to lead to long-term survival benefits. There have been some reports that antagonists may be associated with adverse effects due to histamine release leading to severe allergic reactions. GnRH agonists are currently available in a range of depot formulations, allowing treatment to be tailored to the patient's needs. At present, the antagonists are only available as on-month depot formulations, which may limit their clinical use. Abarelix should be given intramuscularly. It is the first GnRH antagonist which is approved by the FDA for patients with advanced prostate cancer who should be treated under a risk management program. In Europe, abarelix has not been registered yet.

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Treatment Outcome

Early studies on gonadotrophin-releasing hormone (GnRH) antagonists pointed out histamine-mediated anaphylactic reactions as a potential adverse effect of these drug candidates. In this study we have compared the histamine-releasing potential of four approved and marketed antagonists, degarelix, cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples.. Human skin samples were obtained during cosmetic plastic surgery and kept in oxygenated saline solution. The samples were incubated either without or at different concentrations of the antagonists (3, 30 or 300 µg ml(-1) for all, except for ganirelix 1, 10 or 100 µg ml(-1) ). The drug-induced effect was expressed as the increase relative to basal release. The histamine-releasing capacity of the skin was verified by a universal histamine releaser, compound 40/80.. Degarelix had no significant effect on basal histamine release in the 3 to 300 µg ml(-1) concentration range. The effect of ganirelix was moderate causing a nonsignificant increase of 81 ± 27% at the 100 µg ml(-1) concentration. At 30 and 300 µg ml(-1) concentrations abarelix (143 ± 29% and 362 ± 58%, respectively, P < 0.05) and cetrorelix (228 ± 111% and 279 ± 46%, respectively, P < 0.05) caused significantly increased histamine release.. In this ex vivo human skin model, degarelix displayed the lowest capacity to release histamine followed by ganirelix, abarelix and cetrorelix. These findings may provide indirect hints as to the relative likelihood of systemic anaphylactic reactions in clinical settings.

Topics: Gonadotropin-Releasing Hormone; Histamine; Histamine Release; Humans; Oligopeptides; Skin

Three antagonists of gonadotrophin-releasing hormone are currently clinically available. Cetrorelix (Cetrotide) and ganirelix (Orgalutran/Antagon) have been safely used in assisted reproduction since 1999 and 2000 respectively. The structurally similar abarelix (Plenaxis) has been approved for the therapy of advanced androgen sensitive prostate cancer. However, due to the occurrence of allergic reactions, its use is restricted to only a subgroup of patients. These allergic side effects may not be due to abarelix, as the drug itself does not have a strong histamine liberating potential in vitro, but could be attributed to carboxymethylcellulose (CMC), which only Plenaxis, but not Cetrotide or Orgalutran/Antagon contain. CMC is used to obtain the sustained-release characteristics of Plenaxis. Since 1973, numerous case reports and studies have been published regarding allergic reactions and specific immunoglobulin E antibodies against CMC. Thus, the allergic side effects of Plenaxis could be rather due to CMC than to abarelix.

Topics: Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Hypersensitivity; Oligopeptides; Pregnancy

Luteinizing hormone-releasing hormone (LHRH) antagonists work by directly inhibiting LHRH without any initial stimulation of the LHRH receptor. The physiologic response is a direct and rapid decrease in luteinizing hormone, follicle-stimulating hormone, and testosterone without any flare. Although there has been extensive basic-science work on these medications, practical shortcomings have limited clinical studies in prostate cancer. Many of these compounds induce significant histamine-mediated side effects, and until recently, no depot form existed. In 2 recent phase-3 studies comparing abarelix depot with leuprolide and with leuprolide plus bicalutamide, abarelix lowered serum testosterone more quickly. None of the 89 patients on leuprolide alone were castrate on day 8 as opposed to 72% of the 180 patients randomized to abarelix (P <0.001). Similarly, none of the combination group were castrate by day 8, whereas 68% of the abarelix patients were castrate (P <0.001). In addition, 82% of the patients treated with leuprolide and 86% of those given leuprolide/bicalutamide had testosterone surge, whereas none of the abarelix patients did (P <0.001 for both studies). Both phase 2 and phase 3 data show abarelix to be well tolerated. In conclusion, LHRH antagonists offer the physiologic response of orchiectomy without surgery. These medications are well tolerated and a depot form now exists. The expansion of indications for androgen deprivation, such as downsizing or intermittent therapy, could provide many opportunities for their use. Despite these encouraging advances, however, their routine use for advanced prostate cancer may depend on demonstration of a survival advantage in avoiding flare.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Disease-Free Survival; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Male; Oligopeptides; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone; Therapeutics; Treatment Outcome