Sharma, Shringi
(2010)
Pre-Clinical and Clinical Pharmacology of 17alpha-Hydroxyprogesterone caproate (17-OHPC): An Agent for the Prevention of Preterm Birth.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Preterm birth (PTB), birth prior to 37 weeks of gestational age, is a major cause of early childhood mortality and morbidity in the United States. 17alpha-hydroxyprogesterone caproate (17-OHPC) has recently been documented to reduce the incidence of preterm birth. A complete understanding of the pharmacokinetics of 17-OHPC will help in improving clinical outcome. The goal of this dissertation research was to evaluate the preclinical and clinical pharmacology of 17-OHPC in order to optimize the use of this drug in preventing preterm birth.Studies in human liver microsomes and human hepatocytes indicate that 17-OHPC is metabolized by CYP3A. Significant transplacental transfer of 17-OHPC (cord blood to maternal plasma ratio of 0.3) has been observed in pregnant subjects. Studies were performed in fetal hepatocytes to evaluate the metabolism of 17-OHPC. Fetal hepatocytes demonstrate the ability of human fetal liver to metabolize 17-OHPC to fetal specific metabolites, with oxidation being the major metabolic pathway. Further, 17-OHPC and/or its metabolites inhibit bile salt transport in both adult and fetal hepatocytes. To understand the clinical pharmacology of 17-OHPC, pregnant women who received 17-OHPC for clinical reasons were studied and blood samples collected periodically. Wide-interindividual variation was observed in the pharmacokinetics of 17-OHPC in pregnant subjects. The half life of 17-OHPC was 9 days and plasma concentrations of 17-OHPC did not achieve steady state. The race and body mass index of the pregnant subjects affect the plasma levels of 17-OHPC. In conclusion, since CYP3A is involved in the oxidative metabolism of numerous commonly used drugs; 17-OHPC may be involved in clinically relevant metabolic drug interactions with co-administered CYP3A inhibitors or inducers. Since 17-OHPC crosses the placental barrier and reaches the fetus, use of higher doses of 17-OHPC should be approached with caution. The clinical effectiveness of 17-OHPC in preventing preterm birth has been observed in only 33% of the patients. Given the wide interindividual variability, modification of the starting dose based on BMI and race alongwith monitoring of plasma levels and adjustment of subsequent doses accordingly may be needed to improve therapeutic outcomes in the treatment of preterm birth with 17-OHPC.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Venkataramanan, Raman | rv@pitt.edu | RV | | | Committee Member | Day, Billy W | | | | | Committee Member | Poloyac, Samuel M | | | | | Committee Member | Strom, Stephen C | | | | | Committee Member | Caritis, Steve N | | | | | Committee Member | Xie, Wen | | | |
|
| Date: |
11 May 2010 |
| Date Type: |
Completion |
| Defense Date: |
26 October 2009 |
| Approval Date: |
11 May 2010 |
| Submission Date: |
28 April 2010 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
17alpha-Hydroxyprogesterone Caproate; Cytochrome P450; Drug Metabolism; Hepatic Transporters; Modeling and Simulation.; Pharmacokinetics; Preterm Birth |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04282010-030454/, etd-04282010-030454 |
| Date Deposited: |
10 Nov 2011 19:43 |
| Last Modified: |
15 Nov 2016 13:42 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/7718 |
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