A population pharmacokinetic meta-analysis of maraviroc in healthy volunteers and asymptomatic HIV-infected subjects.
OBJECTIVE
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 E(max) 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, V(c) and V(p) 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.
Chan
Phylinda L S
PL
Pharmacometrics, Pfizer Global R&D, Sandwich, UK. phylinda.chan@pfizer.com
Weatherley
Barry
B
McFadyen
Lynn
L
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D065100:CCR5 Receptor Antagonists; D003198:Computer Simulation; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic; D014230:Triazoles / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc