Drug interactions

As a substrate of the CYP3A4 enzyme, maraviroc has potential interactions with other drugs broken down by this enzyme. When maraviroc is given with CYP3A inhibitors, the dose should be reduced to 150 mg twice daily. These drugs include most protease inhibitors (except for tipranavir/ritonavir), ketoconazole, itraconazole, clarithromycin, nefazadone, telithromycin, among others.1 2

Maraviroc dosing must be increased in the presence of a number of drugs due to their effects on its metabolism through the cytochrome p450 system. The 600mg twice-daily dose of maraviroc should be used with all CYP3A inducers (without a CYP3A inhibitor), including efavirenz, rifampin, carbamazepine, phenobarbital, and phenytoin .

Etravirine (Intelence), a potent inducer of the cytochrome p450 CYP3A4 pathway, has been found to speed up the metabolism of maraviroc enormously and it reduces total maraviroc concentrations over a 12-hour period by 53% (AUC12) and peak levels of maraviroc (Cmax) by 60%. Consequently, if a patient is not also taking a potent CYP3A4 inhibitor, such as a protease inhibitor, the recommended clinical dose for maraviroc alongside etravirine is 600mg twice daily. However, if maraviroc is being dosed alongside etravirine and darunavir together, the 150mg twice-daily dose is sufficient. Co-administration of etravirine/darunavir/ritonavir with maraviroc increased the exposure of maraviroc by 210% (AUC12) and peak levels (Cmax) by 77% compared to maraviroc alone.

These results, where the combination of a potent inducer of CYP mediated metabolism (etravirine) and a potent inhibitor of CYP mediated metabolism (darunavir/ritonavir) yields a net increase in maraviroc concentrations, are consistent with previous inducer/inhibitor combination data, where the net effect appears to be inhibition.

Etravirine pharmacokinetic data showed no effect of maraviroc on etravirine pharmacokinetics. Therefore, no dose adjustment of etravirine is necessary. The dose remains 200mg twice daily. Safety data from the study indicated that co-administration of etravirine and maraviroc was generally safe and well tolerated.

Based on these data, the co-administration of maraviroc and etravirine is allowed in patients in the maraviroc expanded access programme when these two investigational drugs are essential to establish a viable treatment regiment.

References

  1. Muirhead G et al. An investigation into the effects of atazanavir and ritonavir boosted atazanavir on the pharmacokinetics of the novel CCR5 inhibitor UK-427,857. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P283, 2004
  2. Abel S et al. An open, randomized, 2-way crossover study to investigate the effects of darunavir/ritonavir on the pharmacokinetics of maraviroc in healthy subjects. Eighth International Workshop on Pharmacology of HIV Therapy, Budapest, abstract 55, 2007
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