Indications
Relugolix is prescribed for the treatment of adult patients with advanced prostate cancer. Additionally, in conjunction with estradiol and norethindrone, it serves as a daily oral treatment for managing heavy menstrual bleeding associated with uterine fibroids in premenopausal women.
Pharmacodynamics
Approximately 56% of patients receiving relugolix achieve castrate-level testosterone concentrations (<50 ng/dL) by the fourth day of therapy, with 97% maintaining these levels throughout a 48-week period. To ensure the desired testosterone concentrations are sustained, relugolix requires once-daily oral administration. As androgen deprivation therapies may extend the QTc interval, caution is advised for patients with a high baseline risk of QTc prolongation, such as those with electrolyte imbalances, congestive heart failure, or taking other QTc-prolonging medications. Due to its mechanism of action and data derived from animal studies, relugolix may pose a risk of fetal harm if administered to pregnant females. Consequently, male patients with female partners should be counseled to use effective contraception during therapy and for two weeks after stopping treatment to prevent unintended fetal exposure.
Absorption
Upon oral administration, the Cmax and AUC of relugolix increase proportionally with single doses. However, with repeated dosing, the AUC maintains proportionality to the dose, while the Cmax increases to a greater extent relative to the dose. For a daily dose of 120 mg, the steady-state AUC and Cmax of relugolix are 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. Relugolix exhibits an absolute oral bioavailability of approximately 12%, with a median Tmax of 2.25 hours post-administration.
Metabolism
The metabolism of relugolix predominantly occurs via the CYP3A subfamily of cytochrome P450 enzymes, with a lesser contribution by CYP2C8.
Mechanism of Action
The mechanism of action of Relugolix involves the interruption of testosterone production, which plays a significant role in the pathogenesis and progression of prostate cancer. Androgen deprivation has been shown to induce cell death and tumor regression in many well-differentiated prostate cancer cell lines, making androgen deprivation therapy (ADT) a standard approach in treating prostate cancer, especially in advanced stages. In males, testosterone is produced by the Leydig cells in the testes, a process stimulated by luteinizing hormone (LH). LH is released by the pituitary gland upon the binding of gonadotropin-releasing hormone (GnRH) to its receptors. Relugolix functions as a competitive antagonist of GnRH receptors, leading to a decrease in LH release and consequently reducing testosterone levels.
