title: 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).
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.
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Hiwot
authors.initials: H
authors.lastname: Hiruy
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fuchs
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Bakshi
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Breakey
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Wutyi S
authors.initials: WS
authors.lastname: Aung
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Manohar
authors.affiliation: 2 Department of Biostatistics, Johns Hopkins School of Public Health , Baltimore, Maryland.
authors.forename: Chen
authors.initials: C
authors.lastname: Yue
authors.affiliation: 2 Department of Biostatistics, Johns Hopkins School of Public Health , Baltimore, Maryland.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Caffo
authors.affiliation: 3 Department of Radiology, Johns Hopkins School of Medicine , Baltimore, Maryland.
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.affiliation: 4 Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Kaleab Z
authors.initials: KZ
authors.lastname: Abebe
authors.affiliation: 5 HJF-DAIDS, a Division of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Contractor to National Institute of Allergy and Infectious Diseases, National Institutes of Health , Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Hans M L
authors.initials: HM
authors.lastname: Spiegel
authors.affiliation: 4 Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|6 Magee-Womens Research Institute , Pittsburgh, Pennsylvania.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Rohan
authors.affiliation: 4 Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|6 Magee-Womens Research Institute , Pittsburgh, Pennsylvania.
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), Johns Hopkins University , Baltimore, Maryland.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
mesh_terms: D000285:Administration, Rectal; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005782:Gels / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D000068698:Tenofovir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047568:Unsafe Sex
chemical_list: D019380:Anti-HIV Agents; D005782:Gels; D000068698:Tenofovir