Indications
Elagolix is utilized as a gonadotropin-releasing hormone (GnRH) receptor antagonist and is specifically prescribed for managing moderate to severe pain associated with endometriosis. Its therapeutic action addresses the debilitating symptoms experienced by individuals suffering from this condition, thus providing significant relief and enhancing the quality of life for sufferers.
Pharmacodynamics
In clinical studies, elagolix has demonstrated a capacity to modulate hormonal activity in women. In a research setting involving a three menstruation cycle study with healthy women, the administration of elagolix at a dosage of 150 mg once daily resulted in an ovulation rate of about 50%, whereas a higher dosage of 200 mg taken twice daily resulted in a reduced ovulation rate of about 32%. Furthermore, Phase 3 clinical trials on women with endometriosis revealed that elagolix elicited a dose-dependent decrease in median estradiol concentrations to approximately 42 pg/mL for the 150 mg regimen and 12 pg/mL for the 200 mg regimen. Importantly, a thorough QTc study involving healthy adult premenopausal women confirmed that even at high elagolix concentrations-17 times higher than those at the therapeutic dose-there was no meaningful prolongation of the QTc interval.
Absorption
Elagolix demonstrates rapid absorption, with a median time to reach maximum concentration (Tmax) of approximately 1 hour. It has been observed that consuming a high-fat meal can significantly impact the pharmacokinetics of elagolix, resulting in reductions in both the area under the concentration-time curve (AUC) and the maximum concentration (Cmax) by as much as 24% and 36%, respectively, when compared to fasting conditions.
Metabolism
The metabolism of elagolix is primarily mediated by the CYP3A group of enzymes, with minor metabolic pathways involving CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs). The primary metabolite of elagolix, identified as NBI-61962, is characterized by low plasma exposure and reduced potency compared to the parent compound, evidenced by a Ki value significantly less potent at 3.5 nM compared to 0.9 nM for elagolix. As such, NBI-61962 is not considered to possess significant biological activity.
Mechanism of Action
Elagolix is a novel, orally-administered nonpeptide small molecule that functions as a gonadotropin-releasing hormone (GnRH) receptor antagonist. It works by competitively binding to GnRH receptors in the pituitary gland, effectively inhibiting endogenous GnRH signaling. This mechanism results in a dose-dependent suppression of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Consequently, the blood levels of the ovarian sex hormones, estradiol and progesterone, are reduced. This reduction is significant because the growth of endometriotic lesions, which can cause symptoms such as menstrual pain, pelvic discomfort between menstrual cycles, and pain during intercourse, is dependent on estrogen. Consequently, by diminishing the levels of these hormones, elagolix helps manage the symptoms associated with endometriosis, which occurs when tissue similar to that found in the uterus grows outside of it, affecting areas like the ovaries, fallopian tubes, bowel, and bladder.
