Drug Interactions between emtricitabine / nelfinavir / tenofovir and Victrelis

MONITOR: Coadministration of boceprevir and some ritonavir-boosted protease inhibitor regimens has been associated with decreased plasma concentrations of both boceprevir and the protease inhibitors. The mechanism of interaction has not been described. In a pharmacokinetic study of 39 healthy volunteers, boceprevir reduced the mean trough plasma concentrations (Cmin) of ritonavir-boosted atazanavir, darunavir, and lopinavir by 49%, 59%, and 43%, respectively. Mean reductions of 34% to 44% were observed in the systemic exposure (AUC) and 25% to 36% were observed in the peak concentration (Cmax) of atazanavir, lopinavir, and darunavir. Conversely, ritonavir-boosted atazanavir did not alter the AUC of boceprevir, whereas ritonavir-boosted darunavir and lopinavir decreased the AUC of boceprevir by 32% and 45%, respectively. When boceprevir (400 mg three times daily for 15 days) was given in combination with ritonavir alone (100 mg once daily for 12 days), boceprevir Cmax and AUC decreased by 27% and 19%, respectively. Data are currently unavailable regarding a potential interaction between boceprevir and other protease inhibitors, whether alone or ritonavir-boosted.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, caution is advised if boceprevir is used in combination with ritonavir-boosted protease inhibitor regimens. Patients coinfected with chronic HCV and HIV who have been started on one of these combinations should be closely monitored for treatment response and potential HCV and HIV virologic rebound. The safety and efficacy of boceprevir has not been established in the HCV/HIV coinfected population. As such, the manufacturer does not recommend the coadministration of boceprevir and ritonavir-boosted HIV protease inhibitors.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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