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

Summary

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 this study was to present the case and develop a model to quantitatively predict the fetal toxicity risk of transdermal administration of ketoprofen.

Methods

Human placenta perfusion studies were conducted to estimate transplacental pharmacokinetic 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 a half that of antipyrine (passive marker). The model and PK parameters predicted almost equivalent mother and fetus drug concentrations at the steady state after transdermal ketoprofen administration in humans. Maximum DA constriction and maximum plasma ketoprofen concentration after administration to rat dams were observed at different times: 4 hours and 1 hour, respectively. The model accurately described the delay of DA constriction profile with respect to 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 human fetus, and fetal toxicity may persist after ketoprofen discontinuation by the mother, as observed in our case.

Conclusion

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

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