Population Pharmacokinetics of Phase 1/2a Data After Oral Tablet Administration of Maraviroc

Background: Maraviroc, an antagonist of the human chemokine receptor CCR5, is being developed for the treatment of HIV-1 infection. Previous findings showed a disproportional increase in AUC with increasing doses and food effects on both bioavailability (F) and absorption rate constant (ka). The aim of this analysis was to describe the population pharmacokinetics (PK) of maraviroc in healthy subjects and HIV-infected patients and to quantify the variability and covariate influences on the variability.

Methods: Plasma concentration data from 365 healthy subjects and 48 asymptomatic HIV-infected patients from 17 Phase 1/2a studies (8951 observations) were included in this analysis. Unit oral (single or multiple) tablet doses of maraviroc ranged from 100 to 1200 mg. Parameter estimation was performed using NONMEM with FOCE.

The influence of demographics (age, weight, race and sex) and HIV status on maraviroc PK was examined using a stepwise forward selection and backwards deletion approach.

Results: A 2 compartment PK model, parameterised as clearance (CL), inter-compartmental clearance (Q), central (V2) and peripheral (V3) volumes, was used to fit the log-transformed plasma concentrations. Absorption was described by first-order process with a lag time. F was partitioned into the extent of absorption (FABS) and fraction escaping first-pass elimination (FHEP) such that F=FABS×FHEP.

A sigmoid Emax function was used to describe the dose effect on FABS and a power function of dose for ka. Food effects on FABS (ABSEmax­ and ED50) were modelled using multiplicative exponential functions. A fractional model was used for the food effect on ka. A continuous time dependent function was used to describe the residual error.

Population parameter estimates (%CV) for the final model were CL 51.5L/h (hepatic extraction ratio 0.662 (8.3%)), V2 132 L (11.5%), V3 277 L (27.8%) and Q 16.4 L/h (30.5%). The peak residual variability occurred at 0.95 hours after a dose, with a maximum value of 74.2% above a constant baseline of 20.2%.

Fasted F increased asymptotically with dose from 0.24 at 100 mg to 0.33 at 600 mg and above. Food reduced F by 43% for a 100 mg dose and approximately 25% at doses of 600 mg and above. There was a dose independent food decrease of 45.3% on ka. The typical Asian subject had a 17.7% greater F than the typical non-Asian subject. A visual predictive check and non-parametric bootstrap evaluation confirmed that the model was a good description of the data.

Conclusions:  The model developed using the pooled data approach adequately describes the PK of maraviroc after oral tablet administration over the clinical dose range. A time dependent residual error model was superior to a standard proportional model. The typical Asian subject had a 26.5% higher AUC than the typical non-Asian subject irrespective of dose, a difference that does not require a dose adjustment. None of the other covariates tested has any clinically relevant effects on exposure.