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 20 mg kg–1 day–1) and rabbits (0, 1.2, 3.6 and 12 mg kg–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 (20 mg kg–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 12 mg kg–1 group, which was regarded as a maternal toxicity. Besides, decreased maternal weight gain also was considered as a minimal maternal toxicity. At 12 mg kg–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 3.6 mg kg–1 groups. Thus, the no‐observed‐adverse‐effect levels of vonoprazan acetate in rabbits are considered 3.6 mg kg–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 12 mg kg–1. These suggested that rabbits treated with vonoprazan at 12 mg kg–1 had slight maternal toxicity and embryo–fetal growth retardation.