Prediction of fetal ductus arteriosus constriction by systemic and local dermatological formulations of NSAIDs based on PK/PD analysis

Aim: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) during the final trimester of pregnancy can cause fetal toxicity, such as ductus arteriosus (DA) constriction. The aim of this study was to predict quantitatively the fetal DA-constrictive effects of NSAIDs after various routes of administration to the mother by means of pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: We evaluated acetaminophen, which is a first-line analgesic/antipyretic for the third trimester of pregnancy, together with the following NSAIDs: indometacin, diclofenac, ibuprofen, flurbiprofen, ketoprofen, loxoprofen, felbinac, naproxen, and celecoxib. Drug concentration data obtained in rats and humans were collected from the literature to calculate PK parameters. Next, the PD parameters for DA constriction in rats were obtained by fitting an E_max model to the DA/pulmonary artery (PA) inner diameter ratio after oral administration of each drug to full-term pregnant rats (data taken from the literature) and the unbound plasma concentration in rat dams estimated from the obtained PK parameters. Finally, the inner DA diameter profile after administration of each drug to human mothers was predicted. Results: This PK/PD model predicted continuous fetal DA constriction in third-trimester women after repeated systemic use of nearly all the NSAIDs evaluated. Local dermatological formulations of NSAIDs were also predicted to potentially cause DA constriction. Conclusion: These results suggest that risk to the fetus should be carefully considered before administration of NSAIDs (especially systemic formulations, but including dermatological formulations) to women in the third trimester of pregnancy.