This proposal describes the Obstetrical-Fetal Pharmacology Research Unit (OPRU) at the University of Pittsburgh. The Pittsburgh OPRU has been highly successful in its original objectives and has contributed to the Network of OPRUs substantially. We have participated in concept proposals, protocol development, recruitment, data analysis and data sharing. The Pittsburgh OPRU has focused its research on the study of 17-hydroxyprogesterone caproate, the only agent at the time shown to reduce the risk of preterm birth in women with a prior preterm birth. We have defined the pharmacology of this agent and have presented our data at national meetings on behalf of the OPRU. In this application, we propose to study the pharmacology of vaginal progestins used in pregnant women with a short cervix. A recent call from the American College of Obstetrics and Gynecology encouraged research to define the proper dosing and formulation for progestin use in pregnancy. We will recruit women between 16 and 22 weeks gestation whose cervix is <30 mm in length. These women are at high risk for preterm birth. We will obtain cervicovaginal fluid prior to treatment and again weekly for 4 weeks after treatment with one of the two progestational agents (Prochieve and Prometrium) with apparent clinical benefit. We will evaluate the pharmacokinetics (PK) of these two agents as well as the pharmacodynamic impact of these agents on cervicovaginal fluid biomarkers including cervical length and density, matrix metalloproteinases, cytokines, and the cervicovaginal proteome. These analyses will allow us to compare the PK of these two progestins, identify their targets and evaluate whether these treatments alter cervical structure. Our second study will evaluate the impact of polymorphisms of drug metabolizing enzymes and pregnancy hormones on the activity of the two major drug metabolizing enzymes CYP, 2C9 and 2D6. We will screen 200 pregnant women and identify those with P450 enzyme polymorphisms known to affect enzyme activity. These polymorphisms commonly lead to a highly variable in enzyme activity. We will administer to these women a cocktail composed of indomethacin and dextromethorphan to evaluate the activity of the cytochrome P450 enzymes once during pregnancy and once postpartum. We will obtain hepatocytes which also express the polymorphisms of interest in CYP, 2C9 and 2D6 and challenge them with estrogen and progesterone to determine the hormone's effects. Finally, we will evaluate the fetal contribution to the variability in activity of these three CYP enzymes by evaluating cord/placental CYP enzymes/polymorphisms.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
5U10HD047905-10
Application #
8600298
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (02))
Program Officer
Ren, Zhaoxia
Project Start
2004-07-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$867,864
Indirect Cost
$243,960
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
119132785
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Caritis, Steve N; Feghali, Maisa N; Grobman, William A et al. (2016) What we have learned about the role of 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth. Semin Perinatol 40:273-80
Costantine, Maged M; Cleary, Kirsten; Hebert, Mary F et al. (2016) Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol 214:720.e1-720.e17
Zhao, Yang; Chen, Hui-Jun; Caritis, Steve et al. (2016) Development and validation of a sensitive liquid chromatographic-tandem mass spectrometric method for the simultaneous analysis of granisetron and 7-hydroxy granisetron in human plasma and urine samples: application in a clinical pharmacokinetic study in Biomed Chromatogr 30:149-54
Ryu, Rachel J; Eyal, Sara; Easterling, Thomas R et al. (2016) Pharmacokinetics of metoprolol during pregnancy and lactation. J Clin Pharmacol 56:581-9
Bastian, Jaime R; Chen, Huijun; Zhang, Hongfei et al. (2016) Dose-adjusted plasma concentrations of sublingual buprenorphine are lower during than after pregnancy. Am J Obstet Gynecol :
Young, Omar M; Shaik, Imam H; Twedt, Roxanna et al. (2015) Pharmacokinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery. Am J Obstet Gynecol 213:541.e1-7
Pillai, Venkateswaran C; Han, Kelong; Beigi, Richard H et al. (2015) Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women. Br J Clin Pharmacol 80:1042-50
Caritis, Steve N; Venkataramanan, Raman; Thom, Elizabeth et al. (2014) Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am J Obstet Gynecol 210:128.e1-6
Grobman, William A; Bailit, Jennifer L; Rice, Madeline Murguia et al. (2014) Frequency of and factors associated with severe maternal morbidity. Obstet Gynecol 123:804-10
Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve (2014) Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol 38:516-22

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