Prediction of sustained fetal toxicity induced by ketoprofen primarily based on PK/PD evaluation utilizing human placental perfusion and rat toxicity information.
Br J Clin Pharmacol. 2017 Nov;83(11):2503-2516
Authors: Tanaka S, Kanagawa T, Momma Okay, Hori S, Satoh H, Nagamatsu T, Fujii T, Kimura T, Sawada Y
AIM: We encountered a case of fetal toxicity as a consequence of ductus arteriosus (DA) constriction in a 36-week pregnant girl who had utilized a number of ketoprofen patches. The goal of the current examine was to current the case and develop a mannequin to foretell quantitatively the fetal toxicity threat of transdermal administration of ketoprofen.
METHODS: Human placenta perfusion research had been performed to estimate transplacental pharmacokinetic (PK) parameters. Utilizing a developed mannequin and these parameters, human fetal plasma focus profiles of ketoprofen administered to moms had been simulated. Utilizing pregnant rats, DA constriction and fetal plasma drug focus after ketoprofen administration had been measured, fitted to an Emax mannequin, and extrapolated to people.
RESULTS: Transplacental switch worth on the regular state of ketoprofen was four.82%, which was roughly half that of antipyrine (passive marker). The mannequin and PK parameters predicted nearly equal mom and fetus drug concentrations at regular state after transdermal ketoprofen administration in people. Most DA constriction and most plasma focus of ketoprofen after administration to rat dams had been noticed at totally different occasions: four h and 1 h, respectively. The mannequin precisely described the delay in DA constriction with respect to the fetal ketoprofen focus profile. The mannequin with impact compartment and the obtained parameters predicted that use of a number of ketoprofen patches might doubtlessly trigger extreme DA constriction within the human fetus, and that fetal toxicity may persist after ketoprofen discontinuation by the mom, as noticed in our case.
CONCLUSION: The current method efficiently described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.
PMID: 28635050 [PubMed – indexed for MEDLINE]