Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Rectal Suppository as a Versatile Platform for Delivering Physicochemically Diverse Antiretrovirals for HIV Prevention

Jhunjhunwala, Kunal (2019) Rectal Suppository as a Versatile Platform for Delivering Physicochemically Diverse Antiretrovirals for HIV Prevention. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF
Restricted to University of Pittsburgh users only until 5 December 2021.

Download (2MB) | Request a Copy

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:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Jhunjhunwala, Kunalksj13@pitt.eduKSJ13
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRohan, Lisalrohan@mwri.magee.edurohanl@pitt.edu
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyac@pitt.edu
Committee MemberVenkataramanan, Ramanrv@pitt.edurv@pitt.edu
Committee MemberEmpey, Phillippempey@pitt.edupempey@pitt.edu
Committee MemberHo, Kenhok2@upmc.edu
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 2019 15:01
URI: http://d-scholarship.pitt.edu/id/eprint/37930

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item