Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy

Venkateswaran C. Pillai, Mansi Shah, Erik Rytting, Tatiana N. Nanovskaya, Xiaoming Wang, Shannon M. Clark, Mahmoud S. Ahmed, Gary D.V. Hankins, Steve N. Caritis, Raman Venkataramanan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Aims: Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. Methods: Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK-based predictions with observed PK profiles. Results: Predicted exposure (AUC0-6h) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0-6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. Conclusion: A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure–response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.

Original languageEnglish (US)
Pages (from-to)271-281
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume88
Issue number1
DOIs
StatePublished - Jan 2022

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy'. Together they form a unique fingerprint.

Cite this