Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data
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- Shingo Tanaka
- Graduate School of Pharmaceutical Science University of Tokyo Tokyo Japan
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- Takeshi Kanagawa
- Department of Maternal‐Fetal Medicine Osaka Medical Center and Research Institute for Maternal and Child Health Osaka Japan
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- Kazuo Momma
- Department of Pediatric Cardiology Tokyo Women's Medical University Hospital Tokyo Japan
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- Satoko Hori
- Graduate School of Pharmaceutical Science University of Tokyo Tokyo Japan
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- Hiroki Satoh
- Graduate School of Pharmaceutical Science University of Tokyo Tokyo Japan
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- Takeshi Nagamatsu
- Department of Obstetrics and Gynecology, Graduate School of Medicine University of Tokyo Tokyo Japan
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- Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Graduate School of Medicine University of Tokyo Tokyo Japan
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- Tadashi Kimura
- Department of Obstetrics and Gynecology Osaka University Graduate School of Medicine Osaka Japan
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- Yasufumi Sawada
- Graduate School of Pharmaceutical Science University of Tokyo Tokyo Japan
抄録
<jats:sec><jats:title>Aim</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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 <jats:italic>E</jats:italic>max model, and extrapolated to humans.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.</jats:p></jats:sec>
収録刊行物
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- British Journal of Clinical Pharmacology
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British Journal of Clinical Pharmacology 83 (11), 2503-2516, 2017-07-27
Wiley