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.