Drug Interactions between emtricitabine / lopinavir / ritonavir / tenofovir and Onxol

MONITOR CLOSELY: Coadministration with certain antiretroviral agents such as protease inhibitors and delavirdine may increase the plasma concentrations and pharmacologic effects of paclitaxel. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of paclitaxel. There have been case reports of life-threatening toxicity and death in patients treated with paclitaxel 100 mg/m2 (a dosage previously found to be safe and effective for AIDS-related Kaposi's sarcoma) who were also receiving highly active antiretroviral therapy (HAART) that included ritonavir, ritonavir/lopinavir, indinavir, saquinavir, and/or delavirdine, all of which are known potent inhibitors of the CYP450 3A4 isoenzyme. Symptoms of toxicity included myalgias, arthralgias, mucositis, febrile neutropenia, leucopenia, thrombocytopenia, infection, alopecia, and ECG abnormalities. A dosage reduction to 60 mg/m2 and concomitant administration with granulocyte colony-stimulating factor (G-CSF) were subsequently required in the patients who recovered.

MANAGEMENT: Caution is advised if paclitaxel is required in patients receiving protease inhibitors and/or delavirdine. A lower initial dosage of paclitaxel may be appropriate. Patients should be closely monitored for the development of dose-related paclitaxel toxicity such as myelosuppression, stomatitis, arthralgia, myalgia, visual disturbances and peripheral neuropathy, and the paclitaxel dosage further adjusted as necessary. Use of repaglinide with the fixed combination of atazanavir-cobicistat is not recommended.

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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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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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