Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo, Japan.
Department of Maternal-Fetal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
Br J Clin Pharmacol. 2017 Nov;83(11):2503-2516. doi: 10.1111/bcp.13352. Epub 2017 Jul 27.
We encountered a case of fetal toxicity due to ductus arteriosus (DA) constriction in a 36-week pregnant woman who had applied multiple ketoprofen patches. The aim of the present study was to present the case and develop a model to predict quantitatively the fetal toxicity risk of transdermal administration of ketoprofen.
Human placenta perfusion studies were conducted to estimate transplacental pharmacokinetic (PK) parameters. Using a developed model and these parameters, human fetal plasma concentration profiles of ketoprofen administered to mothers were simulated. Using pregnant rats, DA constriction and fetal plasma drug concentration after ketoprofen administration were measured, fitted to an Emax model, and extrapolated to humans.
Transplacental transfer value at the steady state of ketoprofen was 4.82%, which was approximately half that of antipyrine (passive marker). The model and PK parameters predicted almost equivalent mother and fetus drug concentrations at steady state after transdermal ketoprofen administration in humans. Maximum DA constriction and maximum plasma concentration of ketoprofen after administration to rat dams were observed at different times: 4 h and 1 h, respectively. The model accurately described the delay in DA constriction with respect to the fetal ketoprofen concentration profile. The model with effect compartment and the obtained parameters predicted that use of multiple ketoprofen patches could potentially cause severe DA constriction in the human fetus, and that fetal toxicity might persist after ketoprofen discontinuation by the mother, as observed in our case.
The present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.
我们遇到了一例 36 周孕妇因动脉导管（DA）收缩而出现胎儿毒性的病例，该孕妇曾多次使用酮洛芬贴片。本研究旨在报道该病例，并建立一个模型来定量预测酮洛芬经皮给药的胎儿毒性风险。
进行了人胎盘灌注研究，以估计胎盘外药物动力学（PK）参数。使用开发的模型和这些参数，模拟了给予母亲的酮洛芬的人体胎儿血浆浓度曲线。使用怀孕大鼠，测量了酮洛芬给药后 DA 收缩和胎儿血浆药物浓度，并将其拟合到 Emax 模型中，并外推至人类。
酮洛芬在稳态时的胎盘转移值为 4.82%，约为非那西丁（被动标志物）的一半。该模型和 PK 参数预测了人类经皮给予酮洛芬后稳态时母亲和胎儿的药物浓度几乎相等。给予大鼠母体后，最大的 DA 收缩和最大的酮洛芬血浆浓度出现在不同的时间：4 小时和 1 小时。该模型准确描述了 DA 收缩相对于胎儿酮洛芬浓度曲线的延迟。具有效应室的模型和获得的参数预测，多次使用酮洛芬贴片可能会导致人类胎儿严重的 DA 收缩，并且在母亲停止使用酮洛芬后，胎儿毒性可能会持续存在，正如我们的病例中观察到的那样。
本方法成功描述了停止经皮给予酮洛芬后持续的胎儿毒性。
