Embryo-fetal toxicity assessment of vonoprazan in rats and rabbits

Vonoprazan is a new potassium-competitive acid blocker to treat acid-related diseases. However, its safety during pregnancy is unclear. The aim of the study was to investigate the potential reproductive toxicity on the embryo-fetal development of vonoprazan. Vonoprazan acetate was administered by intravenous injection to pregnant rats (0, 2, 6 and 20mgkg(-1) day(-1)) and rabbits (0, 1.2, 3.6 and 12mgkg(-1) day(-1)) during the organogenetic period (gestation day 6-15 [rats] and 6-18 [rabbits]). Maternal reproductive endpoints were evaluated, together with effects on fetal growth and morphological development. In rats, no treatment-related effects were found in the highest dose group (20mgkg(-1)) and the maternal plasma exposure was 50-fold the expected clinical human exposure. However, in rabbits, dose-related clinical signs (soft or liquid feces) occurred in the 12mgkg(-1) group, which was regarded as a maternal toxicity. Besides, decreased maternal weight gain also was considered as a minimal maternal toxicity. At 12mgkg(-1), delayed fetal ossification was found as evidence of embryo-fetal growth retardation, which was related to decreased fetal and placental weights. There was no maternal and developmental toxicity in the 1.2 and 3.6mgkg(-1) groups. Thus, the no-observed-adverse-effect levels of vonoprazan acetate in rabbits are considered 3.6mgkg(-1) day(-1), which produced plasma exposure that was about 18-fold human clinical exposure. In the present study, we investigated embryo-fetal developmental toxicity of vonoprazan by intravenous injection to pregnant rats and rabbits during the organogenetic period. Based on results, we found there was no embryo-fetal toxicity in rats. However, in rabbits, clinical signs (soft or liquid feces), decreased maternal weight gain and delayed fetal ossification were found at 12mgkg(-1). These suggested that rabbits treated with vonoprazan at 12mgkg(-1) had slight maternal toxicity and embryo-fetal growth retardation.