当前位置： SCI文献检索 > BRITISH JOURNAL OF CLINICAL PHARMACOLOGY期刊下所有文献 > Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data.

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

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.

journal_name

Br J Clin Pharmacol

journal_title

British journal of clinical pharmacology

authors

Tanaka S,Kanagawa T,Momma K,Hori S,Satoh H,Nagamatsu T,Fujii T,Kimura T,Sawada Y

doi

10.1111/bcp.13352

subject

Has Abstract

pub_date

2017-11-01 00:00:00

pages

2503-2516

issue

eissn

0306-5251

issn

1365-2125

journal_volume

pub_type

杂志文章

在线工具

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