Indomethacin PK and PD Therapy in Pregnancy

Study Overview
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Brief Summary
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This study will follow pregnant women who are taking indomethacin as Standard of Care (SOC) for the indications of preterm labor (PTL), short cervix, or other indications, to evaluate the pharmacokinetics (PK), what the body does to the drug, and pharmacodynamics (PD), effectiveness of the drug in treating the specific intended disease process of this medication. This will help us develop more information for medication dosing specific to pregnant women experiencing preterm labor. Indomethacin is often prescribed to pregnant women presenting with preterm labor or shortened cervix, which places them at risk for preterm labor and delivery. Indomethacin has been used since the 1970s to prolong pregnancy by decreasing uterine contractions. However, despite the widespread use of indomethacin in pregnancy, there is limited information available to help physicians determine how much indomethacin to prescribe and how often to prescribe it.

Detailed Description
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Opportunistic study of indomethacin prescribed to patients per standard of care. Determine the pharmacokinetics, pharmacodynamics and pharmacogenomics of Indomethacin in pregnant patients with the hypothesis that that estradiol levels during pregnancy (12-32 weeks of gestation) and CYP2C9 polymorphisms affect the PK of indomethacin, and subsequently, the response to indomethacin therapy in patients at risk of Preterm birth (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/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 (12-32 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). The investigators will enroll 300 subjects with spontaneous preterm labor (sPTL) or shortened cervix in a prospective opportunistic PK study designed to correlate the PK of indomethacin, patient genotype, and clinical outcomes. The investigators 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 patients 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.

Official Title
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Pharmacokinetic and Pharmacogenomic Approach to Indomethacin Therapy in Pregnancy

Conditions
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Premature Labor, Pregnancy, Premature Birth

Intervention / Treatment
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* Other: Serial blood collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be enrolled in the study, patients must meet all of the following criteria: Age at least 18 years Singleton gestation 12 0/7 to 32 0/7 weeks gestation (see Gestational Age Determination section 3.2.1.1) Patient receiving indomethacin for any of the following diagnoses: Preterm labor: regular uterine contractions with documented cervical change or dilatation ≥ 2 cm and 80% effacement Cervical shortening (< 2.5 cm documented on transvaginal ultrasound) with or without funneling membranes Planned cervical cerclage or emergent cerclage Other condition whereby Indomethacin is indicated Maternal and fetal condition allows anticipated delay of delivery for more than 24 hours - Exclusion Criteria: Exclusion criteria include: Contraindications to indomethacin use (history of maternal bleeding disorder, thrombocytopenia, maternal hepatic, gastrointestinal ulcerative, or renal dysfunction, asthma) Known fetal abnormality, genetic syndrome, or intrauterine fetal demise Anticipated delivery in less than 24 hours, cervical dilatation > 6 cm Preterm premature rupture of membranes Suspected chorioamnionitis Oligohydramnios (DVP < 2 cm) Congenital Uterine anomaly Vaginal bleeding due to suspected placental abruption or placenta previa Planned preterm delivery for maternal/fetal indications Non-reassuring fetal status Planned delivery outside UTMB or participation in another intervention trial which may affect maternal or neonatal outcomes Unsure gestational age due to possibility of intrauterine growth restriction Hematocrit <28% (as determined by most recent result within 1 month of enrollment) Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Single-group<br>Observational opportunistic pharmacokinetic study of 300 pregnant women receiving Indomethacin therapy as standard of care for risk of preterm birth. Receive serial blood collection from IV. | Other: Serial blood collection<br>* Serial blood collection from IV for pharmacokinetic and pharmacodynamic analysis. No drug, device, or biologic intervention. Opportunistic.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational age at delivery | Gestational age at delivery calculated from the first day of last menstrual period unless unsure and then it will be calculated from ultrasound measurements | Enrollment until delivery of the participant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal outcomes | Diagnosed maternal outcomes including oligohydramnios, chorioamnionitis, preterm premature rupture of membranes, venous thromboembolism, pulmonary edema, postpartum hemorrhage, and maternal death | Enrollment until delivery and maternal discharge | 
| Neonatal outcomes | Diagnosed neonatal outcomes including birth weight, APGAR scores, neonatal sepsis, respiratory distress syndrome, patent ductus arteriosis, necrotizing enterocolitis, broncopulmonary dysplasia, paraventricular leukomalacia, intraventricular hemorrhage, fetal, or neonatal death | The earlier of neonatal discharge or up to 120 days postnatal | 
| Neonatal admission to Neonatal intensive care unit (NICU) | Documentation of NICU admission [yes/no] | The earlier of neonatal discharge or up to 120 days postnatal | 
| Length of stay in the Neonatal intensive care unit (NICU) | If admitted to the NICU, number of days in the NICU | The earlier of neonatal discharge or up to 120 days postnatal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Pharmacodynamics, Preterm labor, Preterm birth, Estradiol, Indomethacin, Pregnancy, Short Cervix, CYP2C9 Genotype