Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data

• Published in: British journal of clinical pharmacology 2017-11, Vol.83 (11), p.2503-2516
• Main Authors: Tanaka, Shingo, Kanagawa, Takeshi, Momma, Kazuo, Hori, Satoko, Satoh, Hiroki, Nagamatsu, Takeshi, Fujii, Tomoyuki, Kimura, Tadashi, Sawada, Yasufumi
• Format: Article
• Language: English
• Subjects: Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Antipyrine - pharmacokinetics; Biomarkers, Pharmacological - metabolism; constriction of the ductus arteriosus; Constriction, Pathologic - chemically induced; Drugs in Pregnancy and Lactation; Ductus Arteriosus - drug effects; Ductus Arteriosus - pathology; Female; fetal toxicity; Humans; ketoprofen; Ketoprofen - adverse effects; Ketoprofen - pharmacokinetics; local dermatological formulation; Low Back Pain - drug therapy; Maternal-Fetal Exchange - drug effects; Models, Animal; Models, Biological; Perfusion - methods; PK/PD analysis; Placenta - metabolism; Pregnancy; Pregnancy Complications - drug therapy; Pregnancy Trimester, Third - drug effects; Rats; Rats, Wistar; Risk Assessment - methods; Transdermal Patch - adverse effects
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13352

Aim 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. Methods 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. Results 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. Conclusion The present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.