A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02)

Hiwot Hiruy, Edward Fuchs, Mark A Marzinke, Rahul Bakshi, Jennifer C. Breakey, Wutyi S. Aung, Madhuri Manohar, Chen Yue, Brian S Caffo, Yong Du, Kaleab Z. Abebe, Hans M L Spiegel, Lisa C. Rohan, Ian McGowan, Craig Hendrix

Research output: Contribution to journalArticle

Abstract

CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1% gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111 mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836 mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479 mOsmol/kg). Participants (n = 9) received a single, 4 ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p = 0.006) and RGVF (p = 0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86% (standard deviation 19%) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development.

Original languageEnglish (US)
Pages (from-to)1098-1108
Number of pages11
JournalAIDS Research and Human Retroviruses
Volume31
Issue number11
DOIs
StatePublished - Nov 1 2015

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Tenofovir
Unsafe Sex
Anti-Infective Agents
Glycerol
Pharmacokinetics
Gels
Permeability
Pharmaceutical Preparations
Viruses
Gastrointestinal Agents
Safety
Single-Photon Emission-Computed Tomography
Osmolar Concentration

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

Cite this

A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02). / Hiruy, Hiwot; Fuchs, Edward; Marzinke, Mark A; Bakshi, Rahul; Breakey, Jennifer C.; Aung, Wutyi S.; Manohar, Madhuri; Yue, Chen; Caffo, Brian S; Du, Yong; Abebe, Kaleab Z.; Spiegel, Hans M L; Rohan, Lisa C.; McGowan, Ian; Hendrix, Craig.

In: AIDS Research and Human Retroviruses, Vol. 31, No. 11, 01.11.2015, p. 1098-1108.

Research output: Contribution to journalArticle

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abstract = "CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1{\%} gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111 mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836 mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479 mOsmol/kg). Participants (n = 9) received a single, 4 ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p = 0.006) and RGVF (p = 0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86{\%} (standard deviation 19{\%}) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development.",
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AU - Fuchs, Edward

AU - Marzinke, Mark A

AU - Bakshi, Rahul

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AU - Aung, Wutyi S.

AU - Manohar, Madhuri

AU - Yue, Chen

AU - Caffo, Brian S

AU - Du, Yong

AU - Abebe, Kaleab Z.

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