School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, China.
JiangSu Center for Safety Evaluation of Drugs, Nanjing, 211816, China.
J Appl Toxicol. 2018 Jul;38(7):987-995. doi: 10.1002/jat.3607. Epub 2018 Apr 16.
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 day ) and rabbits (0, 1.2, 3.6 and 12 mg kg day ) 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 ) 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 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 , 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 groups. Thus, the no-observed-adverse-effect levels of vonoprazan acetate in rabbits are considered 3.6 mg kg day , which produced plasma exposure that was about 18-fold human clinical exposure.
伏诺拉生是一种新型钾离子竞争性酸阻滞剂，用于治疗与胃酸相关的疾病。然而，其在妊娠期间的安全性尚不清楚。本研究旨在探讨伏诺拉生对胚胎-胎儿发育的潜在生殖毒性。在器官发生期（大鼠妊娠第 6-15 天和兔子妊娠第 6-18 天），通过静脉注射给予怀孕大鼠（0、2、6 和 20mg/kg 天）和兔子（0、1.2、3.6 和 12mg/kg 天）伏诺拉生醋酸盐。评估了母体生殖终点，以及对胎儿生长和形态发育的影响。在大鼠中，在最高剂量组（20mg/kg）未发现与治疗相关的影响，母体血浆暴露量≥预期临床人体暴露量的 50 倍以上。然而，在兔子中，在 12mg/kg 组中出现了与剂量相关的临床症状（软便或稀便），被认为是母体毒性。此外，母体体重增加减少也被认为是最小的母体毒性。在 12mg/kg 时，发现胎儿骨化延迟，表明胚胎-胎儿生长迟缓，这与胎儿和胎盘重量减轻有关。在 1.2 和 3.6mg/kg 组中，没有母体和发育毒性。因此，在兔子中，伏诺拉生醋酸盐的无观察到不良效应水平（NOAEL）被认为是 3.6mg/kg 天，产生的血浆暴露量约为人体临床暴露量的 18 倍。
