Safety pharmacology of linzagolix: effects on the central nervous, cardiovascular, and respiratory systems

Abstract Background Linzagolix is a potent gonadotropin-releasing hormone (GnRH) antagonist used for the treatment of uterine fibroids and endometriosis. Because of the potential effects of sex hormone suppression on the central nervous, cardiovascular, and respiratory systems, we evaluated the effects of linzagolix on these systems in non-clinical settings to verify its safety. Methods An ICH S7-compliant safety pharmacology program was conducted, including the modified Irwin test in rats, telemetry assessment in conscious cynomolgus monkeys, electrophysiological evaluation of human ether-à-go-go-related gene (hERG) and other cardiac ion channels, action potential recordings in isolated guinea pig papillary muscles, and radioligand binding assays against 75 targets. Results Single oral administration of linzagolix at doses up to 2000 mg/kg showed no detectable effects on the central nervous system (CNS) in female rats. In conscious female monkeys, single oral administration of linzagolix at doses up to 1000 mg/kg showed no detectable effects on the body temperature and did not affect the respiratory system or the blood pressure, heart rate, and electrocardiographic parameters (RR, QRS, PR, QT, and QTcF intervals). In in vitro cardiovascular studies, linzagolix had no effects on the hERG tail current and cardiac ion channel or on action potential parameters in guinea pig papillary muscles. Moreover, linzagolix showed no off-target activity up to a concentration of 10 µmol/L in radioligand binding assays. Conclusions Linzagolix showed no detectable effects on the safety pharmacology endpoints evaluated in this study at concentrations and doses that provided exposures exceeding those achieved at approved therapeutic doses in humans. These findings indicate a low potential for CNS, cardiovascular, respiratory, cardiac electrophysiological, and off-target pharmacological effects under the conditions tested.