Chemical formula: C₂₉H₂₇F₂N₇O₅S Molecular mass: 623.64 g/mol PubChem compound: 10348973
Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to GnRH receptors in the anterior pituitary gland preventing native GnRH from binding and signalling the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Consequently, the production of testosterone from the testes is reduced. In humans, FSH and LH concentrations rapidly decline upon initiating treatment with relugolix and testosterone concentrations are suppressed to below physiologic concentrations. Treatment is not associated with the initial increases in FSH and LH concentrations and subsequently testosterone (“potential symptomatic flare”) observed upon initiation of treatment with a GnRH analogue. Following discontinuation of treatment, pituitary and gonadal hormone concentrations return to physiologic concentrations.
After oral administration of a single 360 mg loading dose, the mean (± standard deviation [± SD]) of AUC0-24 and Cmax of relugolix were 985 (± 742) ng.hr/mL and 215 (± 184) ng/mL, respectively. After administration of a 120 mg dose once daily, the mean (± SD), Cmax, Cavg (average plasma concentration over the 24-hour dosing interval), and Ctrough of relugolix at steady-state were 70 (± 65) ng/mL, 17.0 (± 7) ng/mL and 10.7 (± 4) ng/mL, respectively.
The accumulation of exposure to relugolix upon once daily administration of a 120-mg dose of relugolix is approximately 2-fold. After once daily administration of relugolix following a 360-mg loading dose on the first day of administration, steady state of relugolix is achieved by day 7.
The absorption of relugolix after oral administration is primarily mediated by intestinal P-gp, for which relugolix is a substrate. After oral administration, relugolix is rapidly absorbed, reaching quantifiable concentration by 0.5 hours post-dose followed by one or more subsequent absorption peaks. The median (range) time to Cmax (tmax) of relugolix is 2.25 hours (0.5 to 5.0 hours). The absolute bioavailability of relugolix is 11.6%.
After administration of a single 120-mg dose of relugolix following consumption of a high-calorie, high-fat meal (approximately 800 to 1 000 calories with 500, 220, and 124 from fat, carbohydrate, and protein, respectively), the AUC0-∞ and Cmax were decreased 19% and 21%, respectively. The decreases in exposure to relugolix with food are not considered to be clinically meaningful and therefore relugolix may be administered without regard to food.
Relugolix is 68 to 71% bound to plasma proteins, primarily to albumin and to a lesser extent to α1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78. Based on the apparent volume of distribution (Vz), relugolix distributes widely to tissues. The estimated volume of distribution at steady state (Vss) is 3 900 L.
In vitro studies indicate that the primary CYP enzymes contributing to the overall hepatic oxidative metabolism of relugolix were CYP3A4/5 (45%) > CYP2C8 (37%) > CYP2C19 (<1%) with the oxidative metabolites, Metabolite-A and Metabolite-B, formed by CYP3A4/5 and CYP2C8, respectively.
Once absorbed, approximately 19% of relugolix is eliminated as unchanged active substance in the urine and approximately 80% is eliminated through multiple biotransformation pathways, including CYP3A and CYP2C8 and multiple other minor metabolic pathways, with a minor contribution from biliary secretion of unchanged medicinal product and/or metabolites. Approximately 38% of the administered dose is excreted as metabolites (other than Metabolite-C) in the faeces and urine. Metabolite-C, which is formed by intestinal microflora, is the primary metabolite in faeces (51%) and further reflects non-absorbed drug.
Relugolix is associated with greater than dose-proportional increases in exposure at doses below approximately 80 mg, which is consistent with the dose-dependent saturation of intestinal P-gp and the corresponding decreasing contribution of intestinal P-gp efflux to the oral bioavailability of relugolix as the dose is increased. Upon saturation of intestinal P-gp, a greater proportion of the absorption of relugolix is governed by passive diffusion, and the exposure to relugolix increases in proportion to dose within the 80- to 360-mg dose range. The saturation of intestinal P-gp with higher doses of relugolix is demonstrated by the dose-related increases in exposure to relugolix associated with erythromycin, a strong P-gp inhibitor (and moderate CYP3A inhibitor), where the increases in exposure was less for a 120-mg dose compared with lower doses of relugolix (20 or 40 mg).
Population PK (PopPK) and PopPK/PD analyses suggest that there are no clinically meaningful differences in exposure of relugolix or testosterone concentrations based on age, race or ethnicity, body size (body weight or body mass index) or stage of cancer.
Based upon the dedicated renal impairment studies with 40 mg relugolix, the exposure to relugolix (AUC0-t) was increased by 1.5-fold in patients with moderate renal impairment and by up to 2.0-fold in patients with severe renal impairment as compared to subjects with normal renal function. The increases in patients with moderate renal impairment are not considered to be clinically meaningful. With respect to patients with severe renal impairment, caution is warranted upon once daily administration of a 120-mg dose of relugolix.
The effect of end stage renal disease with or without haemodialysis on the pharmacokinetics of relugolix has not been evaluated. The amount of relugolix removed by haemodialysis is unknown.
After administration of a single 40-mg dose of relugolix to patients with mild or moderate hepatic impairment, the total exposure to relugolix (AUC0-∞) was decreased by 31% or was comparable, respectively, compared to subjects with normal hepatic function. The mean elimination half-life of relugolix in patients with mild or moderate hepatic impairment and healthy control subjects was comparable.
No dose adjustment for relugolix in patients with mild or moderate hepatic impairment is required. The effects of severe hepatic impairment on the pharmacokinetics of relugolix have not been evaluated.
Non-clinical data based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential reveal no special hazard for humans beyond those discussed below.
In human GnRH-receptor knock-in male mice, oral administration of relugolix decreased prostate and seminal vesicle weights at doses ≥3 mg/kg twice daily for 28 days. The effects of relugolix were reversible, except for testis weight, which did not fully recover within 28 days after drug withdrawal. These effects in knock-in male mice are likely associated with the pharmacodynamics of relugolix; however, the relevance of these findings to humans is unknown. In a 39-week repeat dose toxicity study in monkeys, there were no significant effects on male reproductive organs at oral relugolix doses up to 50 mg/kg/day (approximately 36 times the human exposure at the recommended dose of 120 mg daily based on AUC). Relugolix (doses of ≥1 mg/kg) suppressed LH concentrations in castrated male cynomolgus monkeys; however, the suppressive effect of relugolix on LH and sex hormones was not evaluated in the 39-week toxicity study in intact monkeys. Therefore, the relevance of the lack of effect on reproductive organs in intact male monkeys to humans is unknown.
In pregnant rabbits orally dosed with relugolix during the period of organogenesis, spontaneous abortion and total litter loss were observed at exposure levels (AUC) less than that achieved at the recommended human dose of 120 mg/day. No effects on embryofoetal development were observed in rats; however, relugolix does not interact significantly with GnRH receptors in that species.
In lactating rats administered a single oral dose of 30 mg/kg radiolabelled relugolix on post-partum day 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higher than in plasma at 2 hours post-dose decreasing to low levels by 48 hours post-dose. The majority of relugolix-derived radioactivity in milk consisted of unchanged relugolix.
Environmental risk assessment studies have shown that relugolix may pose a risk for the aquatic compartment.
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