Indomethacin PK and PD Therapy in Pregnancy

Status:	Active, not recruiting
Conditions:	Women's Studies, Women's Studies
Therapuetic Areas:	Reproductive
Healthy:	No
Age Range:	18 - Any
Updated:	1/6/2019
Start Date:	May 2015
End Date:	May 2019

Pharmacokinetic and Pharmacogenomic Approach to Indomethacin Therapy in Pregnancy

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.

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.

Inclusion Criteria:

To be enrolled in the study, patients must meet all of the following criteria:

1. Age at least 18 years

2. Singleton gestation

3. 12 0/7 to 32 0/7 weeks gestation (see Gestational Age Determination section 3.2.1.1)

4. Patient receiving indomethacin for any of the following diagnoses:

1. Preterm labor: regular uterine contractions with documented cervical change or
dilatation ≥ 2 cm and 80% effacement

2. Cervical shortening (< 2.5 cm documented on transvaginal ultrasound) with or
without funneling membranes

3. Planned cervical cerclage or emergent cerclage

4. Other condition whereby Indomethacin is indicated

5. Maternal and fetal condition allows anticipated delay of delivery for more than 24
hours -

Exclusion Criteria:

- Exclusion criteria include:

1. Contraindications to indomethacin use (history of maternal bleeding disorder,
thrombocytopenia, maternal hepatic, gastrointestinal ulcerative, or renal
dysfunction, asthma)

2. Known fetal abnormality, genetic syndrome, or intrauterine fetal demise

3. Anticipated delivery in less than 24 hours, cervical dilatation > 6 cm

4. Preterm premature rupture of membranes

5. Suspected chorioamnionitis

6. Oligohydramnios (DVP < 2 cm)

7. Congenital Uterine anomaly

8. Vaginal bleeding due to suspected placental abruption or placenta previa

9. Planned preterm delivery for maternal/fetal indications

10. Non-reassuring fetal status

11. Planned delivery outside UTMB or participation in another intervention trial
which may affect maternal or neonatal outcomes

12. Unsure gestational age due to possibility of intrauterine growth restriction

13. Hematocrit <28% (as determined by most recent result within 1 month of
enrollment)

14. Prisoners

We found this trial at

sites

University of Texas Medical Branch, Dept of OB/GYN

Galveston, Texas 77555

Principal Investigator: Gary Hankins, MD

Phone: 409-747-8234

from

Galveston, TX