A Randomized, Open-Label, Crossover Phase 1 Safety and Pharmacokinetic Study of Oral Maraviroc and Maraviroc 1% Gel (the CHARM-03 Study)

Abstract

The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK (p < .0001). Only oral MVC was associated with limited protection in the rectal explant HIV challenge model (p < .05). There were no immunological changes in RT, and all products were acceptable to participants. In conclusion, all products were found to be safe and acceptable and did not induce local inflammation. The lack of ex vivo efficacy demonstrated in study samples may be due to rapid disassociation of MVC from the explant tissue. ClinicalTrials.gov Identifier: NCT02346084.

Keywords: HIV; maraviroc; microbicide; prevention; rectal.

FIG. 1.

CHARM-03 study design for female participants. CHARM-03 female study participants sequenced through three open-label drug exposure phases in a randomized manner (oral, rectal, and vaginal drug administration). F, female; R, rectal; N, number; Bx, biopsy; CV, cervical; MVC, maraviroc; CHARM-03, Combination HIV Antiretroviral Rectal Microbicide-3. Color images are available online.

FIG. 2.

Compartmental PK profile following oral, rectal, and vaginal dosing (median and interquartile range). Tissue concentration of MVC was standardized by biopsy weight. Cervicovaginal and RFs were standardized by the weight of fluid extracted from the collection device. LLOQs were as follows: plasma MVC, 0.1 ng/mL; RF MVC, 0.5 ng/sponge; endocervical/vaginal fluid MVC, 0.05 ng/swab; rectal/CT MVC, 0.05 ng/sample. CT, cervical tissue; PK, pharmacokinetic; RF, rectal fluid. Color images are available online.

FIG. 3.

Rectal and CT explant HIV infection. Following viral challenge, cervical and rectal explant tissues were cultured for 14 days. Supernatant HIV-1 p24 was quantified every three to four days until the end of the culture period. Data are expressed as the cumulative concentration of HIV-1 p24 per mL per mg of tissue. (A) Rectal tissue explants, (B) CT explants, *p ≤ .05. Color images are available online.