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

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 or dual CYP450 3A4 and P-glycoprotein (P-gp) inhibitors may significantly increase the plasma concentrations of docetaxel, which is a substrate of both CYP450 3A4 and P-gp. In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2. In addition, a suspected interaction with amiodarone was described in a case report involving a 77-year-old woman with HER2-positive invasive ductal breast cancer on long-term amiodarone therapy who developed increasing abdominal discomfort and skin lesions during 4 cycles of paclitaxel (80 mg/m2 weekly) and trastuzumab. A subsequent switch to docetaxel (100 mg or 75 mg/m2 weekly) led to the development of severe skin and mucosal toxicity, requiring hospitalization 8 days after the first docetaxel dose was administered. Analysis of two blood samples taken 9 and 10 days after docetaxel administration showed an approximately fivefold increase in its AUC as well as the presence of paclitaxel in unquantifiable levels, 20 and 21 days after it was last administered. In another case report, a 79-year-old man was hospitalized with fever, diarrhea, and grade 4 stomatitis and neutropenia after receiving a third cycle of docetaxel (35 mg/m2 on days 1 and 8 every 21 days) for metastatic androgen-independent prostate cancer while on dronedarone therapy (400 mg twice daily), which had been commenced 24 days earlier due to recurrence of atrial fibrillation. Docetaxel was still detectable in a plasma sample taken 24 days after it was last administered, at a concentration of approximately 2.4 ng/mL, even though its terminal half-life is about 12 hours. Unfortunately, the patient died after deterioration of his condition and multiple infectious complications. The authors of these case reports propose that, in addition to CYP450 3A4 inhibition, P-gp inhibition due to amiodarone and dronedarone may also have contributed to the interaction.

MANAGEMENT: Concomitant use of docetaxel with CYP450 3A4 inhibitors, particularly potent inhibitors or dual CYP450 3A4 and P-gp inhibitors such as itraconazole, ketoconazole, posaconazole, conivaptan, ceritinib, idelalisib, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics, should generally be avoided. Some authorities recommend avoiding concomitant use of docetaxel during and for 2 weeks after treatment with itraconazole. If concomitant use is required, a reduced dosage of docetaxel should be considered. Based on extrapolation from the pharmacokinetic study in 7 cancer patients, a 50% reduction in the docetaxel dose may be reasonable. Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea.

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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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