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Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention

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Abstract

Purpose

Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission.

Methods

0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety.

Results

The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 μg/cm2/min1/2), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 μg/cm2/min1/2). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe.

Conclusions

The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.

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Abbreviations

API:

Active pharmaceutical ingredient

DPV:

Dapivirine

HIV:

Human immunodeficiency virus

IPM:

International partnership for microbicides

MTN:

Microbicide trials network

MVC:

Maraviroc

NDRI:

National disease research interchange

NNRTI:

Non-nucleoside reverse transcriptase inhibitor

NRTI:

Nucleotide reverse transcriptase inhibitor

PrEP:

Pre-exposure prophylaxis

TER:

Trans-epithelial resistance

TFA:

Trifluoroacetic acid

TFV:

Tenofovir

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank the University of Pittsburgh Medical Center Tissue Procurement program for their work in obtaining the ectocervical and colorectal tissues and the patients for their willingness to participate in research. We acknowledge use of ectocervical tissue provided by the NDRI with support from National Institutes of Health grant 5 U42 RR006042. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. BD and JN are employees of the International Partnership of Microbicides and provided drug substances and study products, but had no role in study design, data collection and analysis. All other authors declare that they have no conflict of interest.

Funding

The work presented here was supported by a grant to the Microbicide Trials Network which is funded by the National Institute of Allergy and Infectious Diseases (UM1 AI068633, UM1 AI106707 and UM1 AI068615), the Eunice Kennedy Shriver National Institute of Child Health and Development, and the National Institute of Mental Health, all of the U.S. National Institutes of Health.

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Authors and Affiliations

  1. University of Pittsburgh, 204 Craft Avenue, Pittsburgh, Pennsylvania, 15213, USA

    Charlene S. Dezzutti, Bernard Moncla & Lisa C. Rohan

  2. Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA

    Charlene S. Dezzutti, Sarah Yandura, Lin Wang, Bernard Moncla & Lisa C. Rohan

  3. Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Elizabeth A. Teeple & Elizabeth R. Brown

  4. International Partnership for Microbicides, Silver Springs, Maryland, USA

    Brid Devlin & Jeremy Nuttall

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  1. Charlene S. Dezzutti
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  2. Sarah Yandura
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Correspondence to Charlene S. Dezzutti.

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Dezzutti, C.S., Yandura, S., Wang, L. et al. Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention. Pharm Res 32, 3768–3781 (2015). https://doi.org/10.1007/s11095-015-1738-7

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  • DOI: https://doi.org/10.1007/s11095-015-1738-7

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