A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV-positive subjects

Br J Clin Pharmacol. 2008 Apr;65 Suppl 1(Suppl 1):54-9. doi: 10.1111/j.1365-2125.2008.03136.x.


Aims: Maraviroc (UK-427 857), an antagonist of the CCR5 receptor with potent anti-HIV activity, was recently approved for use in treatment-experienced patients infected with CCR5-tropic HIV-1. The aim of this study was to evaluate the effect of selected commonly used antiretroviral therapy (ART) combinations on the pharmacokinetics of a single oral dose of maraviroc 300 mg in HIV-positive subjects compared with historical controls.

Methods: In this study, four cohorts of HIV-positive patients (n = 8 each) receiving one of the following combination therapies were recruited: cohort 1--efavirenz + Combivir (lamivudine/zidovudine); cohort 2--efavirenz + didanosine + tenofovir; cohort 3--nevirapine + lamivudine + tenofovir; cohort 4--Kaletra (lopinavir/ritonavir) + stavudine + lamivudine. Subjects continued on their prescribed ART and also received a single oral dose of maraviroc 300 mg. Serial blood samples and urine for determination of maraviroc pharmacokinetics were collected over 12 h postdose. Plasma pharmacokinetic parameters from this study were compared with historical data generated in HIV-positive subjects receiving maraviroc monotherapy in a Phase IIa study.

Results: A total of 29 subjects were recruited (eight each in cohorts 1-3, and five in cohort 4). The geometric mean ratios for AUC(12) and C(max) for each treatment group compared with maraviroc monotherapy were: 47% and 67% (cohort 1); 48% and 76% (cohort 2); 101% and 154% (cohort 3); and 265% and 180% (cohort 4), respectively. T(max) was similar in all treatment groups. Mean values for renal clearance ranged from 8.2 l h(-1) (cohort 1) to 13.2 l h(-1) (cohort 4). There were no renal clearance data collected in the comparator study.

Conclusions: The results of this study support those previously seen in healthy volunteer studies that showed that efavirenz reduces maraviroc exposure, whereas lopinavir/ritonavir increases maraviroc exposure. These data also suggest that nevirapine does not lead to a clinically significant effect on maraviroc pharmacokinetics.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Anti-Retroviral Agents / blood
  • Anti-Retroviral Agents / pharmacology*
  • Anti-Retroviral Agents / urine
  • Area Under Curve
  • CCR5 Receptor Antagonists*
  • Cyclohexanes / blood
  • Cyclohexanes / pharmacokinetics*
  • Cyclohexanes / urine
  • Drug Interactions
  • Drug Therapy, Combination
  • HIV Infections / drug therapy*
  • HIV Infections / metabolism
  • HIV-1 / drug effects*
  • Humans
  • Male
  • Maraviroc
  • Middle Aged
  • Receptors, CCR5 / blood
  • Triazoles / blood
  • Triazoles / pharmacokinetics*
  • Triazoles / urine


  • Anti-Retroviral Agents
  • CCR5 Receptor Antagonists
  • Cyclohexanes
  • Receptors, CCR5
  • Triazoles
  • Maraviroc