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 lg h/mL, mean peak plasma concentration (Cmax) was 1.02 ± 0.49 lg/mL, and mean time to reach Cmax (tmax) 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.

Placental control of drug delivery

“…First, the amount of time that had passed between the last dose of a drug and sampling of the maternal plasma is more likely to affect the maternal concentration than the effect of time on the cord blood concentration of the drug. Perhaps due to a reduced fetal capacity for biotransformation or processes effecting the transfer of drugs across the placenta in the fetal-to-maternal direction, the maternal clearance of some medications is substantially faster than fetal clearance, which means that the maternal levels of a drug would decline more rapidly than fetal levels [12,19]. If a maternal plasma sample is taken soon after the dose was administered, the maternal level would be high, whereas if the sample were taken several hours after the dose, the maternal level would be much lower.…”

“…Fetal concentrations of the drug could be higher at steady state than after a single dose due to the accumulation of a drug that cannot be as rapidly cleared from the fetal circulation. Therefore, fetal-to-maternal ratios could be higher at steady state than following a single dose [12]. …”

“…The expression and function of drug metabolizing enzymes can also change significantly during pregnancy, some as the result of increased estrogen levels [11]. It is important to consider whether dose adjustments would be necessary to account for the pregnancy-associated changes affecting the pharmacokinetics of certain medications [12]. …”

Pharmacologic studies in vulnerable populations: Using the pediatric experience

“…The use of collaborative networks, including the NICHD-sponsored, 4-site Obstetric-Fetal Pharmacology Research Units (OPRU) Network (2004-present) has already proven successful in the determination of differences in drug clearance between pregnant and non-pregnant women for drugs such as indomethacin and oseltamivir. 23,24 Expansion of this network and creation of others based on existing infrastructure at large academic centers can improve expertise, encourage multidisciplinary involvement in research teams, and increase access to pregnant patients in efforts to improve clinical research in pregnancy. Furthermore, implementation of multi-site protocols with broad inclusion criteria aimed at the study of multiple drugs, will improve efficiency in gathering data for clinical use in pregnancy.…”

Lessons Learned in Pediatric Clinical Research to Evaluate Safe and Effective Use of Drugs in Pregnancy

“…This 4-site network in the U.S. has generated important findings related to differences in drug clearance between pregnant and non-pregnant women for numerous drugs, including indomethacin and oseltamivir. 15,16 …”