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CHARM-03:SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF ORAL AND TOPICAL MARAVIROC
Ian McGowan1, Rhonda M. Brand1, Jarret C. Engstrom2, Aaron Siegel2, Ashley Myerski2, Cindy Jacobson2, Mark A. Marzinke3, Craig W. Hendrix3, Alex Rinehart4, John Steytler5, Charlene S. Dezzutti1, Nicola Richardson-Harman6, Hans M. Spiegel7, Ross Cranston1
1University of Pittsburgh, Pittsburgh, PA, USA,2Magee–Womens Research Institute, Pittsburgh, PA, USA,3Johns Hopkins Hospital, Baltimore, MD, USA,4ViiV Healthcare, Research Triangle Park, NC, USA,5International Partnership for Microbicides, Paarl, South Africa,6Alpha StatConsult, LLC, Damascus, MD, USA,7NIAID, Rockville, MD, USA
Maraviroc (MVC) is being evaluated as a HIV-1 PrEP agent. In the non-human primate model, oral MVC did not provide protection from SHIV162p3 rectal challenge whereas topical rectal MVC was protective. Phase 1/2 studies have not demonstrated significant viral inhibition in the ex vivo / in vitro colorectal explant challenge model. The purpose of the CHARM-03 study was to characterize the safety, pharmacokinetic (PK), and pharmacodynamic profile of MVC following oral, vaginal, and rectal administration.
Healthy HIV-1 uninfected men and women with homozygous wildtype CCR5 genotype were enrolled into a randomized open label crossover trial in which they received 300 mg oral MVC daily for 8 consecutive days, 1% MVC rectal gel for 8 consecutive days, and female participants received daily vaginally administered MVC 1% gel for 8 consecutive days. Each product administration was followed by a washout period of 14 to 21 days. Blood and tissue (cervical and rectal) were collected prior to and +2, +24 and +48 hours after the final dose of study product. One biopsy was snap frozen for PK and a second biopsy was incubated in culture medium for 2 hours before being snap frozen for PK. Tissue biopsies were challenged with HIV-1BaL as previously described (McGowan I et al. Lancet HIV 2016).
Twenty participants (11 male) were enrolled in the study. Twenty-five adverse events (24 Grade 1 and one Grade 2) were reported in 11 participants. Rectal PK at Day 8 of dosing (mean ± SD) was: oral tablet (7.9 ± 7.2 ng/mg), rectal gel (29.2 ± 36.5 ng/mg), and vaginal gel (0.1 ± 0.1 ng/mg). HIV-1 p24 inhibition was seen only in rectal tissue after oral dosing and only 1-2 hours post dose (p<0.05); inhibition was not detected in cervicovaginal tissue after oral dosing, nor in either tissue site with rectal or vaginal dosing. Pairwise comparison of snap frozen versus cultured tissue showed significant loss of MVC during 2 hours incubation (median Log10 ± IQR) in rectal tissue following both oral tablet (1.16 ± 0.7) and rectal gel (0.96 ±1.04) and in cervical tissue following vaginal gel (1.34 ± 0.79) (p<0.0001) Figure 1.
Oral and topical MVC were safe and well tolerated and the use of oral MVC was associated with colorectal explant viral inhibition. MVC significantly disassociated from explant tissue during incubation which may account for the absence of viral suppression after rectal and vaginal gel exposure.