Jhunjhunwala, Kunal
(2019)
Rectal Suppository as a Versatile Platform for Delivering Physicochemically Diverse Antiretrovirals for HIV Prevention.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
When reflecting on new Human Immunodeficiency Virus (HIV-1) infections across the globe, we find that men who have sex with men (MSM) are disproportionally impacted, especially in developed nations. Several studies have now shown that the chances of HIV-1 transmission through receptive anal intercourse (RAI) is about 10 times higher compared to vaginal intercourse. Therefore, new strategies are needed to combat rectal transmission of HIV-1. However, the rectal anatomy and physiology, limit dosage form options for drug delivery to this compartment. Suppositories offer several advantages over other rectally administered dosage forms, from a formulation as well as user acceptability perspective. Considering these advantages, this dissertation aims to explore application of the rectal suppository platform to deliver antiretroviral (ARV) drugs as pre-exposure prophylaxis (PrEP) for HIV prevention. In addition, since HIV-1 treatment and products typically utilize more than one ARV, we also explored the potential of developing a suppository product which co-delivered multiple ARV candidates.
Several suppository bases were screened to obtain a desired set of suppository characteristics. From this analysis, two bases (Witepsol H15 and PEG 3350:1000:400 at ratio 60:30:10) were chosen for further evaluation. Additionally, based on factors such as the mechanism of action, physicochemical properties, and drug-resistance profile, tenofovir (TFV), tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) were selected as the lead ARV candidates. The suppositories were manufactured, characterized and tested for stability as per ICH guidelines. Combination suppositories (TFV and EVG) were manufactured and their pharmacokinetics following a single dose administration was evaluated in a non-human primate (NHP) model. Rectal fluid, tissues (biopsies) and plasma samples were collected to determine the drug exposure achieved using each test suppository dosage form. Furthermore, to evaluate whether there was any pharmacokinetic advantage gained by replacing tenofovir with its prodrug TAF, combination suppositories (TAF and EVG) were manufactured and evaluated in the same NHP model. The results from both these studies confirmed comparable or in some cases better drug exposure achieved in vivo using a suppository dosage form as compared to other dosage forms such as gels and enemas. The studies presented in this dissertation provide a proof of concept that suppositories can be used as potential ARV drug delivery platform for PrEP from HIV.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Jhunjhunwala, Kunal | ksj13@pitt.edu | KSJ13 | |
|
| ETD Committee: |
|
| Date: |
5 December 2019 |
| Date Type: |
Publication |
| Defense Date: |
11 October 2019 |
| Approval Date: |
5 December 2019 |
| Submission Date: |
3 December 2019 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
165 |
| 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: |
HIV, pre-exposure prophylaxis, suppository |
| Date Deposited: |
05 Dec 2019 15:01 |
| Last Modified: |
05 Dec 2021 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37930 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}