Physicians following HIV-positive patients in an expanded access program for Pfizer’s experimental entry inhibitorCelsentri (maraviroc) are being informed of significant drug interactions with Tibotec’s etravirine and Prezista (darunavir). The caution, issued in the form of a “Dear Doctor” letter from Pfizer, outlines specific Celsentri dosing changes if the drug is combined with these medications.
Researchers have determined that etravirine, an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) also available in an expanded access program, is a powerful inducer of Celsentri’s metabolism. As a result, Celsentri is rapidly processed and removed from the body, causing the blood concentration of the drug to fall below the level needed to effectively inhibit HIV replication.
Conversely, Tibotec’s Prezista—like most other protease inhibitors, especially when combined with low-dose Norvir (ritonavir)—is an inhibitor of Celsentri’s metabolism. This likely results in raised blood concentrations of the drug, which can increase the risk of Celsentri-related side effects.
When combined with etravirine—provided that protease inhibitors and other metabolism blockers are not being used—the Celsentri dose should 600mg twice daily. When combined with Prezista plus Norvir, regardless of whether or not etravirine is used, the Celsentri dose should be 150mg twice daily.
When Celsentri is used with HIV medications that don't have an
effect on its rate of metabolism, the dose is
300mg twice daily.
The new Celsentri dosing recommendations are based on a drug interaction study recently completed by Pfizer. Combined with etravirine, peak blood concentrations (Cmax) decrease by 53% and concentrations over a 12-hour period (AUC12) drop by 60%. When combined with etravirine and Prezista/Norvir, Celsentri’s Cmax increases by 77% and its AUC12 soars 210%.
Celsentri was not found to have a significant effect on etravirine blood concentrations. In turn, no etravirine dose adjustment is necessary—it remains 200mg twice a day.
Safety data from the study suggests that the coadministration of etravirine and Celsentri was generally safe and well tolerated.
