Safety and dose-finding trial of tadalafil administered for fetal growth restriction: A phase-1 clinical study
Safety and dose-finding trial of tadalafil administered for fetal growth restriction: A phase-1 clinical study
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DOI：
10.1111/jog.13345
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发表时间：
2017-07-01
影响因子：
1.6
通讯作者：
Ikeda, Tomoaki
中科院分区：
文献类型：
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作者：
Kubo, Michiko;Tanaka, Hiroaki;Ikeda, Tomoaki
目的设计一项他达拉非治疗胎儿生长受限(FGR)的安全性和剂量发现试验。如果在三个病例中的一个或多个病例中观察到重大不良事件，将由安全评价委员会对其与他达拉非的关系进行检查。如果这些新病例中的一个或多个表现出相同的不良事件，试验将完全停止。如果没有有害的副作用，试验将扩大到三个病例，每天20毫克，方案将继续，如10毫克/天剂量。有6例患者因剂量较大而尝试40 mg/d的剂量。结果研究对象为FGR孕妇。所有剂量的孕妇不良事件都被记录为至少一个一级不良事件，因为从母亲的角度来看，他达拉非是可以接受的。然而，每天40毫克的剂量增加了1级不良事件的数量。唯一的胎儿不良事件是一例胎儿宫内死亡，与脐带的绒状插入有关。新生儿不良事件与他达拉非剂量无关，但在早产儿中更常见，因此与婴儿早产有关。结论这项安全性和剂量发现试验表明，他达拉非对患有FGR的孕妇和胎儿具有良好的安全性。
Aim We designed a safety and dose-finding trial of tadalafil administered for fetal growth restriction (FGR).Methods Three cases were initially commenced on 10 mg/day and monitored for major adverse events. Should a major adverse event be observed in one or more of the three cases, an examination into its relation with tadalafil would be conducted by a safety evaluation committee. If one or more of these new cases exhibited the same adverse event, the trial would be stopped completely. If there were no harmful side-effects, the trial would be extended to three cases at 20 mg/day, and the protocol would continue as in the 10-mg/day dose. The 40-mg/day dosage was tried in six cases as the dosage was considered to be high.Results The study population consisted of pregnant women with FGR. Maternal adverse events in all doses were recorded as least one grade 1 adverse events, as tadalafil was considered acceptable from the viewpoint of the mothers. However, a dose of 40 mg/day increased the number of grade 1 adverse events. The only fetal adverse event was a case of intrauterine fetal death related to the velamentous insertion of the umbilical cord. Neonatal adverse events showed no correlation to tadalafil dose, but were found more frequently in preterm births and, therefore, were correlated to infant prematurity.Conclusion This safety and dose-finding trial showed that tadalafil had a favorable safety profile for pregnant women and fetuses with FGR.