Pharmacokinetics of indomethacin in pregnancy

Abstract

Background and objectives: Although indomethacin has been widely used for the treatment of preterm labor over the past 40 years, there are few reports regarding its pharmacokinetics in pregnant women.

Methods: This opportunistic study assessed the steady-state pharmacokinetics of indomethacin in pregnant subjects to whom an oral dose of 25 mg every 6 h was prescribed. Indomethacin concentrations in plasma and urine were analyzed by a validated high-performance liquid chromatography method with mass spectrometric detection.

Results: The mean area under the plasma concentration versus time curve at steady state (AUCss) was 1.91 ± 0.53 μg·h/mL, mean peak plasma concentration (C max) was 1.02 ± 0.49 μg/mL, and mean time to reach C max (t max) was 1.3 ± 0.7 h. The mean apparent clearance at steady state was 14.5 ± 5.5 L/h, which is higher than the apparent clearance reported in the literature for non-pregnant subjects. Indomethacin crosses the placenta; the mean fetal/maternal ratio from five sets of cord blood samples collected at delivery was 4.0 ± 1.1.

Conclusions: Further studies are needed to determine whether any dose adjustments are necessary as a result of the increased clearance of indomethacin during pregnancy.

Fig. 1

Mean steady-state plasma concentration versus time profile for 25 pregnant subjects receiving 25-mg oral doses of indomethacin every 6 h. Error bars represent the standard deviation

Fig. 2

Comparison of cord blood and maternal concentrations of indomethacin at the time of delivery from five mother-child pairs. a Concentrations of indomethacin in maternal and cord blood versus the time between the last dose of indomethacin and delivery. b Cord blood indomethacin concentrations (z axis) versus the interval between the last dose and delivery (y axis) and the number of consecutive days of indomethacin dosing prior to delivery (x axis)