Indomethacin Pharmacokinetics and Pharmacodynamics in Pregnancies With Preterm Labor: The Need for Dose-Ranging Trials

Stephen J. Balevic, Daniel Weiner, Christoph P. Hornik, Michael Cohen-Wolkowiez, Daniel Gonzalez, Xiaoming Wang, Meixiang Xu, Sherif Z. Abdel-Rahman, Erik Rytting

Research output: Contribution to journalArticlepeer-review

Abstract

The use of indomethacin to delay delivery in preterm labor (PTL) is widely accepted; however, the optimal dosage of indomethacin in pregnancy is unknown. Here, we perform population pharmacokinetic (PK) and pharmacodynamic (PD) analyses, characterize the plasma disposition of indomethacin in pregnant women with PTL, and relate indomethacin exposure to delayed delivery and maternal/neonatal safety. We analyzed plasma and urine samples collected from a multicenter, prospective, opportunistic PK/PD study of indomethacin in pregnant women 12-32 weeks gestation admitted with PTL. Ninety-four participants with 639 plasma concentrations for indomethacin were included in the analysis. The final population PK (popPK) model for indomethacin was a 2-compartment structural model with first-order absorption and elimination and a covariate effect of body mass index on apparent oral clearance. We observed a 21%-60% increase in apparent oral clearance observed during pregnancy. There was no clear association between indomethacin exposure and maternal or neonatal safety outcomes, or with the magnitude of delayed delivery; however, 96.7% of women treated with indomethacin had a delivery that was delayed at least 48 hours. Given the changes to indomethacin apparent oral clearance during pregnancy, and the lack of relationship between indomethacin exposure and safety, dose-finding studies of indomethacin in pregnant women with PTL may help clarify the most safe and efficacious dosage and duration of indomethacin.

Original languageEnglish (US)
JournalJournal of clinical pharmacology
DOIs
StateAccepted/In press - 2024
Externally publishedYes

Keywords

  • indomethacin
  • pharmacokinetics
  • pregnancy
  • preterm labor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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