Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women

Abstract

Objective: To compare single- and multiple-dose maraviroc exposures in cervicovaginal fluid (CVF) and vaginal tissue (VT) with blood plasma (BP) and quantify maraviroc protein binding in CVF.

Design: Open-label pharmacokinetic study.

Methods: In 12 HIV-negative women, 7 paired CVF and BP samples were collected over 12 hours after 1 maraviroc dose. Subjects then received maraviroc twice daily for 7 days. After the last dose, subjects underwent CVF and BP sampling as on day 1, with additional sampling during terminal elimination. VT biopsies were obtained at steady state.

Results: Day 1 and day 7 median maraviroc CVF AUCtau were 1.9- and 2.7-fold higher, respectively, than BP. On day 1, 6 of 12 subjects had detectable maraviroc CVF concentrations within 1 hour; 12 of 12 were detectable within 2 hours, and all exceeded the protein-free IC90. On day 7, maraviroc CVF protein binding was 7.6% and the VT AUCtau was 1.9-fold higher than BP. Maraviroc CVF concentrations 72 hours after dose and BP concentrations 12 hours after dose were similar.

Conclusions: Higher maraviroc exposure in the female genital tract provides a pharmacologic basis for further evaluation of chemokine receptor 5 antagonists in HIV infection prophylaxis. This is the first study to report antiretroviral VT concentrations, CVF protein binding, and CVF terminal elimination.

FIGURE 1

A, Day 1 (single dose) concentration–time profile of maraviroc in BP and CVF for 12 subjects over the 12-hour dosing interval [data presented as median (IQR)]. B, Day 7 (multiple dose) concentration–time profile of maraviroc in BP and CVF for 10 subjects over the 12-hour dosing interval [data presented as median (IQR)]. C, Trough (C_min) concentration of maraviroc in BP and CVF over days 2–6 of dosing [data presented as median (IQR)]. For all CVF time points, n = 12; for BP, day 3 included 11 subjects and day 5 included 6 subjects. D, Individual CVF:BP AUC ratios calculated over a day 1 and day 7 dosing interval. IQR, interquartile range.

FIGURE 2

A, VT concentrations of maraviroc in relation to BP and CVF concentrations, within a dosing interval on day 7 (multiple dose) [data presented as median (IQR)]. An estimated tissue density of 1.05 g/mL was used to convert VT concentration from nanograms per gram to nanograms per milliliter. B, Day 7 (multiple dose) concentration–time profile of maraviroc in BP and CVF over 72 hours post-dose for 10 subjects [data presented as median (IQR)]. IQR, interquartile range.