Pharmacokinetic and pharmacogenomic approach to indomethacin therapy in pregnancy



 DESCRIPTION (provided by applicant): Preterm birth (PTB) is a major cause of neonatal morbidity and mortality worldwide. Indomethacin has been widely used in patients with spontaneous preterm labor (sPTL) as a tocolytic in order to delay delivery and prolong pregnancy. However, the dose of indomethacin used for tocolysis is based on experience gained from trials and clinical practice and not from rigorous pharmacokinetic (PK)/pharmacodynamic (PD) studies. Pilot data obtained in our laboratory revealed significantly higher apparent clearance of indomethacin in African American pregnant women as compared to White non-Hispanic pregnant women. Furthermore, among African Americans, women who delivered before 34 weeks of gestation had higher clearance of indomethacin as compared to women who delivered after 34 weeks. According to the literature, the higher clearance of indomethacin observed in African American women could be attributed to higher levels of estradiol that may induce activity of the major enzyme CYP2C9 metabolizing indomethacin, as well as to polymorphisms of the CYP2C9 gene. Therefore, we hypothesize that estradiol levels at mid-pregnancy and CYP2C9 polymorphisms affect the PK of indomethacin, and subsequently, the response to indomethacin therapy in patients at risk of PTB. This hypothesis will be tested with the following specific aims: (1) Determine the PK of indomethacin in pregnant women at risk of PTB and its PD effects on reducing the rate of PTB before 34 weeks of gestation, as well as any associations between the PK and secondary maternal/fetal/neonatal clinical outcomes; (2) Determine the effects of maternal levels of estradiol in mid-pregnancy and CYP2C9 polymorphisms on indomethacin biotransformation to O-desmethylindomethacin in pregnant patients; (3) Construct a population PK/PD model of indomethacin in patients at risk of PTB (18-32 weeks of gestation) in order to optimize the dose and the dosing frequency for indomethacin prescribed to each individual based on covariates such as race/ethnicity, CYP2C9 genotype, gestational age, estradiol levels, smoking status, and body mass index (BMI). We will enroll 300 subjects in a prospective opportunistic PK study designed to correlate the PK of indomethacin, patient genotype, and clinical outcomes. We will merge dosing, sampling, demographic, and clinical information with the drug concentration data and use population PK methodologies to analyze the data using nonlinear mixed effect modeling. Quantification of the differences within and between individuals allows for identification of covariates (e.g., CYP2C9 genotype, estradiol levels, BMI, etc.) that can explain variability and affect drug exposure. These covariates, if significant, can then be used in the future to optimize dosing in individual patient at risk for PTB. Achieving this goal of individualized indomethacin therapy could have a significant impact on clinical practice and improve maternal and neonatal outcomes.