Pfizer has written to the doctors of patients receiving its new anti-HIV drug maraviroc (Celsentri) through an expanded access programme to warn them about interactions between maraviroc and two drugs made by Tibotec, etravirine (TMC125) and darunavir (Prezista), that will require maraviroc dose adjustments.
Maraviroc dosing must be adjusted in the presence of a number of drugs due to their effects on its metabolism through the cytochrome p450 system.
Etravirine, a potent inducer of the cytochrome p450 CYP3A4 pathway, has been found to speed up the metabolism of maraviroc enormously, Pfizer said this week. It reduces total maraviroc concentrations over a 12-hour period by 53% (AUC12) and peak levels of maraviroc (Cmax) by 60%.
Therefore, says Ashley Milton, director of Clinical Pharmacology at Pfizer, if a patient isn't also taking a potent CYP3A4 inhibitors 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, a dose reduction to 150mg twice daily is necessary.
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 TMC125 is necessary. The dose remains 200mg twice daily.
Safety data from the study indicated that co-administration of TMC125 and maraviroc was generally safe and well tolerated.
Based on these data the coadministration 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 regimen for the patient, says Pfizer.