A population pharmacokinetic meta‐analysis of maraviroc in healthy volunteers and asymptomatic HIV‐infected subjects

• Published in: British journal of clinical pharmacology 2008-04, Vol.65 (s1), p.76-85
• Main Authors: Chan, Phylinda L. S., Weatherley, Barry, McFadyen, Lynn
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anti-HIV Agents - pharmacokinetics; CCR5; CCR5 Receptor Antagonists; Computer Simulation; Cyclohexanes - pharmacokinetics; Female; HIV; HIV Infections - drug therapy; Humans; Male; maraviroc; Middle Aged; Models, Biological; Models, Statistical; NONMEM; Original; population pharmacokinetics; Randomized Controlled Trials as Topic; Triazoles - pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2008.03139.x

AIMS To develop a population pharmacokinetic model for maraviroc, a noncompetitive CCR5 antagonist, after oral administration of tablets to healthy volunteers and asymptomatic HIV‐infected subjects and to quantify the inherent variability and influence of covariates on the parameters of the model. METHODS Rich pharmacokinetic data available from 15 studies in healthy volunteers (n = 365) and two studies in asymptomatic HIV‐infected subjects (n = 48) were analysed using NONMEM. Maraviroc was administered as single or multiple oral tablet doses under fasted and fed conditions. Doses ranged from 100 to 1800 mg day−1. RESULTS A two‐compartment model parameterized to separate out absorption and clearance components on bioavailability was used. Absorption was described by a lagged first‐order process. A sigmoid Emax model described the effect of dose on absorption. A visual predictive check and nonparametric bootstrap evaluation confirmed that the model was a good description of the data. Typical CL, Vc and Vp values for a 30‐year‐old non‐Asian are 51.5 l h−1, 132 l and 277 l, respectively. CONCLUSIONS For the typical non‐Asian subject, fasted bioavailability increased asymptotically with dose from 24% at 100 mg to 33% at 600 mg. A high‐fat meal taken with maraviroc reduced exposure by 43% for a 100‐mg dose to approximately 25% at doses of 600 mg. The typical Asian subject had a 26.5% higher AUC than the typical non‐Asian subject irrespective of dose, a difference not considered to be clinically relevant. None of the other covariates tested had any clinically relevant effects on exposure.