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 AUC τ 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 IC 90 . On day 7, maraviroc CVF protein binding was 7.6% and the VT AUC τ 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.

Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy

“…S2 in the supplemental material). In semen, concentrations of all the antiretrovirals measured 24 h after drug administration (C24h) were in the same range as those measured in HIV-1-infected patients under suppressive HAART (70-74) and, as described in other body fluids (75,76), were well above C24h in blood, suggesting better stability (Fig. 6A and B).…”

HIV Prevention by Oral Preexposure Prophylaxis

“…Antiretrovirals differ greatly in their ability to penetrate mucosal tissues or secretions Dumond et al 2007Dumond et al , 2009Jones et al 2009;Brown et al 2011). In general, highly protein-bound compounds do not gain access to these secondary compartments because of their affinity for plasma proteins such as albumin and a 1 -acid glycoprotein.…”

“…For example, maraviroc, a cellular entry inhibitor that shows 75% protein binding in blood plasma, has high penetration into cervicovaginal fluid (CVF) and vaginal tissue. After 7 d of dosing at 300 mg of maraviroc twice daily, the areas under the concentration -time curve (AUCs) in CVF and vaginal tissue are 2.7 and 1.9 times higher, respectively, than blood plasma (Dumond et al 2009). Raltegravir, an integrase inhibitor that is 83% protein bound in plasma, has also been shown to penetrate well in the female genital tract: The concentrations of the drug in CVF after multiple dosing are up to twofold higher than those in plasma (Jones et al 2009).…”

“…The concentrations of albumin and a 1 -acid glycoprotein in cervicovaginal fluid are ,1% of the values in plasma (Salas Herrera et al 1991). Although the protein binding of drugs in genital secretions has not been extensively evaluated, maraviroc has recently been shown to have 10-fold less protein binding in CVF than in plasma (7.5% vs. 75%) (Dumond et al 2009). This phenomenon must be considered in pharmacokinetic-pharmacodynamic analysis of ARV prevention strategies, as the free drug concentration represents the fraction of drug available to be active against HIV infection.…”

Short Communication: Limited Anti-HIV-1 Activity of Maraviroc in Mucosal Tissues

“…Maraviroc (MVC) is the first antiretroviral (ARV) smallmolecule CCR5 inhibitor 3 to have been included in highly active antiretroviral therapy (HAART) and is currently being considered in the field of prevention as a candidate for oral pre-exposure prophylaxis (PrEP) or for topical application as a microbicide. Formulated as a microbicide gel, MVC has shown promising pharmacological results in humans and nonhuman primates (NHPs) 4,5 and efficacy in NHPs when tested as a vaginal gel. 6,7 To model different potential prevention dosing conditions, we tested drug efficacy before viral challenge (3-h drug exposure), before and after challenge (24-h drug exposure), or continuous drug exposure mimicking sustained release.…”