Chaphekar, Nupur
(2019)
PRELIMINARY SAFETY EVALUATION OF 17-HYDROXYPROGESTERONE CAPROATE (17-OHPC) INTRAVAGINAL GEL IN PREGNANT RATS.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
PRELIMINARY SAFETY EVALUATION OF 17-HYDROXYPROGESTERONE CAPROATE (17-OHPC) INTRAVAGINAL GEL IN PREGNANT RATS
Nupur Chaphekar, MS
University of Pittsburgh, 2019
Preterm birth is defined as delivery before 37 weeks of gestation. The only current FDA approved treatment option for the prevention of preterm birth is a 250 mg weekly intramuscular injection of an oily formulation of 17-hydroxyprogesterone caproate (17-OHPC) sold under the trade name Makena®. This treatment strategy requires the subjects to make weekly hospital visits and in addition, pain at injection site is a common complaint. 17-OHPC has been shown to be effective only in 33% of women receiving the treatment. Recently, the FDA approved 17-OHPC in a subcutaneous auto injector device (Makena auto-injector). The auto-injector device offers some potential advantages, but patients still need to visit the hospital to receive the injection. The injection site pain continues to be a problem with the autoinjector. An alternate route which is safe and effective is needed to help overcome these limitations and benefit a larger proportion of the patient population.
Studies from our laboratory have evaluated the pharmacokinetics of 17-OHPC after different routes of administration in rats. The oral route of administration is not practical due to a low bioavailability of 3%. Vaginal administration is a logical choice and we have developed a gel formulation for 17-OHPC for vaginal administration. In a preliminary unpublished study from our lab, we have shown the feasibility and safety of intravaginal administration of 17-OHPC in female
non-pregnant rats and rabbits. The goal of the current study was to evaluate the safety of 17-OHPC intravaginal gel in pregnant rats.
A gel formulation of 17-OHPC was administered intravaginally to adult female pregnant sprague dawley rats starting from day 10 of gestation. The treatment was continued until the day of delivery. After delivery, both rats and pups were euthanized. Blood and vital organs were collected from the mother for the estimation of 17-OHPC concentrations using LC-MS-MS and for histopathology. Pups were fixed in formalin and the histopathology was assessed.
Repeated intravaginal application did not alter body weight gain in the mothers. After vaginal administration, 17-OHPC showed high local tissue levels at the site of application with undetectable levels in plasma in the mothers. There were no gross differences in histopathology between control and treated rats indicating no tissue damage at the site of application in the mothers. The weight of the pups from both the groups showed no statistically significant differences. There was no damage to any of the vital organs in the pups and there were no differences in the number of pups delivered in control or treated mothers. This indicates that the intravaginal administration of 17-OHPC gel appears to be safe in pregnant rats and the pups delivered. Having established the safety, we plan to initiate a safety study in non-pregnant women before conducting a clinical study in pregnant women.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Chaphekar, Nupur | nkc8@pitt.edu | nkc8 | |
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| ETD Committee: |
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| Date: |
10 April 2019 |
| Date Type: |
Publication |
| Defense Date: |
2 April 2019 |
| Approval Date: |
10 April 2019 |
| Submission Date: |
10 April 2019 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
53 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
N/A |
| Date Deposited: |
10 Apr 2019 18:11 |
| Last Modified: |
10 Apr 2020 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/36439 |
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