Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men

Abstract

Background: Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence.

Methods: A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2.

Results: SP AUCs were ∼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations >2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were ∼70% lower than BP, but saliva concentrations correlated with BP (r(2) = 0.58).

Conclusions: More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence.

Clinical trials registration: NCT00775294.

Figures

Figure 1.

Maraviroc concentrations after a single dose (PK1)—geometric mean (90%CI) maraviroc concentrations in rectal tissue (diamonds), BP (squares), SP (circles), and saliva (triangles) on study day 1. Times are staggered to improve visualization of the data. Geometric mean sampling times are used for SP and RT.

Figure 2.

Maraviroc concentrations after multiple doses (PK2)—maraviroc concentrations in rectal tissue (diamonds) and SP (circles) on study day 7 and 8 and in BP (squares) and saliva (triangles) on study day 8. Times are staggered to improve visualization of the data. Geometric mean sampling times are used for SP and RT.

Figure 3.

Relative antiretroviral exposure in the male genital tract versus protein binding in blood plasma–the relative exposure (SP:BP) of 15 antiretrovirals in the male genital tract negatively correlates with their respective reported protein binding in blood plasma (rho = −.59; P = .02). Tenofovir (TNF), Stavudine (D4T), Lamivudine (3TC), Zidovudine (AZT), Abacavir (ABC), Indinavir (IDV), Nevirapine (NVP), Maraviroc (MVC), Amprenavir (APV), Darunavir (DRV), Nelfinavir (NFV), Lopinavir (LPV), Efavirenz (EFV), Ritonavir (RTV), Saquinavir (SQV). [25, 26]