Orgovyx: genotox, carcinogenicity and repro: done or skipped?

“Relugolix was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay nor clastogenic in the in vitro chromosomal aberration assay and in vivo rat bone marrow micronucleus assay.”

“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.”

“In an embryo-fetal development study in rabbits, oral administration of relugolix during the period of organogenesis resulted in embryo-fetal lethality at the highest dose tested, 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).”

“In safety pharmacology studies, there were no relugolix-related adverse effects on the central nervous and respiratory systems in rats at doses up to 2000 mg/kg. While relugolix was a low-potency hERG blocker in vitro (IC50 = 9.7 µg/mL), a single dose of relugolix in monkeys resulted in QT/QTc prolongation of up to 47 msec at ≥ 100 mg/kg (90 times the human Cmax based on toxicokinetics from a 4-week repeat-dose monkey study).”

“Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.”

“Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.”

“Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.”

“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.”

“TAK-385 was evaluated at doses up to 100 mg/kg/day in mice and up to 600 mg/kg/day in rats in the 2-year carcinogenicity studies.”

“Relugolix inhibited hERG potassium channel current by 3.4%, 20.5% and 78.5% at 0.3, 3 and 30 µg/mL respectively and with an IC50 of 9.7 µg/mL (15.5 μM). This IC50 is approximately 123-fold higher than the mean total steady state Cmax of 79.1 ng/mL”