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

Shingo Tanaka, Takeshi Kanagawa, Kazuo Momma, Satoko Hori, Hiroki Satoh, Takeshi Nagamatsu, Tomoyuki Fujii, Tadashi Kimura, Yasufumi Sawada

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2503-2516
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume83
Issue number11
DOIs
Publication statusPublished - 2017 Nov 1
Externally publishedYes

Fingerprint

Ketoprofen
Pharmacokinetics
Perfusion
Ductus Arteriosus
Constriction
Cutaneous Administration
Mothers
Fetus
Antipyrine
Pharmaceutical Preparations
Placenta
Pregnant Women

Keywords

  • constriction of the ductus arteriosus
  • fetal toxicity
  • ketoprofen
  • local dermatological formulation
  • PK/PD analysis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data. / Tanaka, Shingo; Kanagawa, Takeshi; Momma, Kazuo; Hori, Satoko; Satoh, Hiroki; Nagamatsu, Takeshi; Fujii, Tomoyuki; Kimura, Tadashi; Sawada, Yasufumi.

In: British Journal of Clinical Pharmacology, Vol. 83, No. 11, 01.11.2017, p. 2503-2516.

Research output: Contribution to journalArticle

Tanaka, S, Kanagawa, T, Momma, K, Hori, S, Satoh, H, Nagamatsu, T, Fujii, T, Kimura, T & Sawada, Y 2017, 'Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data', British Journal of Clinical Pharmacology, vol. 83, no. 11, pp. 2503-2516. https://doi.org/10.1111/bcp.13352
Tanaka, Shingo ; Kanagawa, Takeshi ; Momma, Kazuo ; Hori, Satoko ; Satoh, Hiroki ; Nagamatsu, Takeshi ; Fujii, Tomoyuki ; Kimura, Tadashi ; Sawada, Yasufumi. / Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data. In: British Journal of Clinical Pharmacology. 2017 ; Vol. 83, No. 11. pp. 2503-2516.
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AU - Hori, Satoko

AU - Satoh, Hiroki

AU - Nagamatsu, Takeshi

AU - Fujii, Tomoyuki

AU - Kimura, Tadashi

AU - Sawada, Yasufumi

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AB - 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.

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