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Antiretrovirals for Prevention: Maraviroc Exposure in the Semen and Rectal Tissue of Healthy Male Volunteers after Single and Multiple Dosing
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Kevin Brown*, K Patterson, S Malone, N Shaheen, H Prince, J Dumond, M Spacek, P Heidt, M Cohen, and A Kashuba
Univ of North Carolina at Chapel Hill, US
Background: MVC is a CCR5 antagonist approved for use in patients with R5-tropic HIV infection. The pharmacology of ARV in multiple compartments provides insight into the development of ARV resistance and prevention of sexual transmission of HIV. This is the first study to investigate MVC exposures in semen (SE) and rectal tissues (RT).
Methods: An open-label pharmacokinetic (PK) study was performed in 12 HIV negative men receiving MVC 300mg BID for 8 days. Seven blood plasma (BP) samples were collected over a 12 hr interval on Day 1 (PK1) and Day 7/8 (PK2); 1 RT sample from each subject was collected during PK1 and PK2. For PK1, 2 semen samples paired with 2 blood plasma samples were collected from each subject. For PK2, 6 semen samples were collected over 2 days paired with 6 blood plasma samples. MVC concentrations were measured by validated LC/MS assays with a 1 ng/mL LLQ. Data were analyzed by noncompartmental methods (WinNonlin 6). A RT density of 1.05 g/mL was assumed for comparisons. Demographics and PK parameters are reported as median (range), and PK ratios are reported as geometric means (GMR) (90% CI).
Results: Subject age was 22 (20 to 42) yrs and BMI was 25.1 (20.2 to 29.1) kg/m2. Eight were Caucasian. PK results are reported in the following table:
The MVC accumulation ratio (PK2 AUC12h: PK1 AUC12h) was 1.29 for BP, 1.34 for semen, and 4.10 for rectal tissue. After single and multiple dosing, MVC AUCs in semen were 56% and 62% of BP, respectively. After a single and multiple dosing, MVC AUC in RT was 9-fold and 28-fold that observed in blood plasma.
Conclusions: Contrary to our previous observation of 3-fold higher MVC exposures in cervicovaginal fluid compared to blood plasma, MVC exposures in semen were 38% lower than blood plasma after multiple doses. However, if MVC protein binding in semen is low, mucosal exposure of MVC may still exceed the protein-free HIV IC90 (0.5 ng/mL). Rectal tissue exposure after multiple dosing was 10-fold higher than what we previously measured for vaginal tissue (2-fold higher than blood plasma). This finding is likely due to fecal elimination and mucous trapping of MVC. These data suggest that MVC may prevent or reduce propagation of HIV in the gastrointestinal tract. Virologic and immunologic investigations are ongoing.
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