Abstract

This Proposal is part of a Program project grant focusing on combination antiretroviral microbicides formulated in a gels optimized or vaginal use and for rectal use for the prevention of sexually-tranmitted HIV infection. This project includes a series of pre-Phase I studies that will assess the pharmacokinetic, pharmacodynamic (anti-HIV efficacy and toxicity), and acceptability characteristics of a combination microbicide simultaneously.
Specific Aim 1. Methods Validation. Develop and validate assays for 0528 in blood, tissue, and luminal fluid, improve tenofovir intracellular assay sensitivity, verify compatibility of radiolabels with gel formulations, and cross-validate HIV explant methods with existing IP/CP funded labs for comparability.
Specific Aim 2. Impact of Rectal Gel Volume on Distribution Comparative pre-Phase I Study. Compare colonic distribution and permeability with 3.5 mL v. 10 mL rectal placebo gel to inform final dose formulation for pre-Phase I clinical studies in Aim 3 &Aim 4.
Specific Aim 3. Exploratory 0528 gel pre-Phase I PK/PD/Acceptability Study. Compare the spatiotemporal distribution (cervicovaginal, rectal, systemic), explant tissue anti-HIV effect, toxicological assessment, and acceptability of the 0528 candidate gel formulation for vaginal and rectal dosing in an exploratory pre-Phase I clinical study.
Specific Aim 4. Exploratory combination 0528/tenofovir pre-Phase I PK/PD/Acceptability Study. Compare the spatiotemporal distribution (cervicovaginal, rectal, systemic), explant tissue anti-HIV effect, toxicological assessment, and acceptability of the 0528/tenofovir candidate gel formulation for vaginal and rectal dosing in an exploratory pre-Phase I clinical study.

Public Health Relevance

These studies will provide critical data to assess the combination 0528/tenofovir vaginal and rectal gel using antiviral effect, safety, pharmacokinetics, and acceptability measurements. These data domains will enable rational decision making regarding further pursuit of this novel ARV combination which includes an active agent (0528) not currently licensed for use in HIV treatment and suitable for both vaginal and rectal use.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI101961-01
Application #
8404840
Study Section
Special Emphasis Panel (ZAI1-ESB-A (M2))
Project Start
2012-06-22
Project End
2017-05-31
Budget Start
2012-06-22
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$575,586
Indirect Cost
$93,815

  Institution

Name
Imquest Biosciences
Department
Type
DUNS #
146051664
City
Frederick
State
MD
Country
United States
Zip Code
21704

  Publications

Weld, Ethel D; Hiruy, Hiwot; Guthrie, Kate Morrow et al. (2017) A Comparative Pre-Phase I Study of the Impact of Gel Vehicle Volume on Distal Colon Distribution, User Experience, and Acceptability. AIDS Res Hum Retroviruses 33:440-447
Ham, Anthony S; Buckheit Jr, Robert W (2017) Designing and developing suppository formulations for anti-HIV drug delivery. Ther Deliv 8:805-817
Gao, Y; Yuan, A; Chuchuen, O et al. (2015) Vaginal deployment and tenofovir delivery by microbicide gels. Drug Deliv Transl Res 5:279-94
Ham, Anthony S; Nugent, Sean T; Peters, Jennifer J et al. (2015) The rational design and development of a dual chamber vaginal/rectal microbicide gel formulation for HIV prevention. Antiviral Res 120:153-64
Katz, David F; Yuan, Andrew; Gao, Yajing (2015) Vaginal drug distribution modeling. Adv Drug Deliv Rev 92:2-13
Pereira, Lara E; Mesquita, Pedro M M; Ham, Anthony et al. (2015) Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques. Antimicrob Agents Chemother 60:1393-400