A phase 1 randomized, open label, rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of three formulations of tenofovir 1% Gel (the CHARM-01 study)

Mcgowan, I and Cranston, RD and Duffill, K and Siegel, A and Engstrom, JC and Nikiforov, A and Jacobson, C and Rehman, KK and Elliott, J and Khanukhova, E and Abebe, K and Mauck, C and Spiegel, HML and Dezzutti, CS and Rohan, LC and Marzinke, MA and Hiruy, H and Hendrix, CW and Richardson-Harman, N and Anton, PA (2015) A phase 1 randomized, open label, rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of three formulations of tenofovir 1% Gel (the CHARM-01 study). PLoS ONE, 10 (5).

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Abstract

Objectives: The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study. Methods: Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial. Results: All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/10⁶ cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection. Conclusions: All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection. Trial Registration: ClinicalTrials.gov NCT01575405.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Mcgowan, I imcgowan@pitt.edu IMCGOWAN Cranston, RD rdc27@pitt.edu RDC27 Duffill, K Siegel, A Engstrom, JC Nikiforov, A Jacobson, C Rehman, KK Elliott, J Khanukhova, E Abebe, K kza3@pitt.edu KZA3 Mauck, C Spiegel, HML Dezzutti, CS csd13@pitt.edu CSD13 Rohan, LC Marzinke, MA Hiruy, H Hendrix, CW Richardson-Harman, N Anton, PA
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Lama, Javier R UNSPECIFIED UNSPECIFIED UNSPECIFIED
Centers:	Other Centers, Institutes, Offices, or Units > Magee-Women's Research Institute
Date:	5 May 2015
Date Type:	Publication
Access Restriction:	No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title:	PLoS ONE
Volume:	10
Number:	5
DOI or Unique Handle:	10.1371/journal.pone.0125363
Institution:	University of Pittsburgh
Refereed:	Yes
Date Deposited:	23 Aug 2016 14:05
Last Modified:	30 Mar 2021 13:56
URI:	http://d-scholarship.pitt.edu/id/eprint/28481

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