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

@entity1 @entity137 @entity146 @entity15833 @entity365
UNASSIGNED: CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied @entity15833 1% gel candidate rectal microbicides of varying osmolalities: @entity365 ( @entity365 ) (3111   mOsmol/kg), the @entity146 ( @entity146 ) (836   mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479   mOsmol/kg). @entity1 (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 @entity15833 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 @entity365 group compared to RF (p   =   0.006) and @entity146 (p   =   0.048). In the absence of simulated unprotected RAI, @entity365 had up to 3.8-fold greater systemic @entity15833 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 @entity146 . 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 @entity146 and RF formulation, with the exception of a higher plasma @entity15833 concentration of @entity146 in the absence of simulated unprotected RAI. @entity365 had the most adverse events, highest plasma @entity15833 concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and @entity146 formulations. There were no major differences between RF and @entity146 formulations. Simultaneous assessment of @entity137 , systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development.
