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

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or P-glycoprotein may significantly increase the plasma concentrations of vinca alkaloids, which are substrates of both the hepatic microsomal isoenzyme and intracellular efflux transporter. Although pharmacokinetic data are not available, the interaction has been associated with severe and life-threatening toxicities in both adult and pediatric cancer patients. Paralytic ileus, intestinal obstruction and perforation, laryngeal nerve paresis requiring mechanical ventilation, neurogenic bladder, paresthesia, paralysis, hypotension, hypertension, heart failure, hyponatremia secondary to SIADH, seizures, profound myelosuppression, and septic shock have been reported. Most cases have involved vincristine or vinblastine in combination with itraconazole. However, the interaction has also been reported with other known potent inhibitors such as clarithromycin, erythromycin, cyclosporine, posaconazole, voriconazole and ritonavir, as well as less potent ones such as nifedipine and isoniazid. In adults with acute lymphoblastic leukemia receiving vincristine as part of their chemotherapeutic regimen, neurotoxicity (paresthesia, muscle weakness, and paralytic ileus) was more severe and occurred earlier and more frequently in 14 patients coadministered itraconazole 400 mg/day for antifungal prophylaxis than in 460 previous patients who did not receive itraconazole (29% vs. 6%). Similarly, in a retrospective cohort study consisting of 25 patients receiving 59 courses of vinorelbine-containing chemotherapy, the incidence of grade 3 or 4 neutropenia was 63.2% in patients who were coadministered clarithromycin, compared to 27.5% in those who did not receive clarithromycin. The incidence of grade 4 neutropenia was also higher in the clarithromycin group, 31.6% vs. 2.5%. Four patients who had received vinorelbine both with and without clarithromycin had lower neutrophil counts during clarithromycin coadministration. A retrospective study to assess vincristine dosing and toxicity in combination with azoles found that vincristine dosing modifications (i.e., dose reductions, dose delays, therapy discontinuation) occurred in 58.6% of patients who received concomitant azole therapy (n=29) compared to 23.8% of patients who did not (n=21). The mean dose reduction of vincristine when combined with an azole was 46.5%. Symptoms of decreased peristalsis were also more common in the azole group, 65.5% vs. 28.6%. The individual incidence was 50%, 75%, and 66.6% in patients receiving fluconazole, voriconazole, and posaconazole, respectively. In addition, patients in the azole group were more likely to have an incomplete course of vincristine, 48.3% vs. 9.5%. Most reported cases of toxicity have been reversible following discontinuation of the CYP450 3A4 inhibitor, and many of the patients tolerated their chemotherapy in the absence of the inhibitor or after dose adjustment. In one incident, however, a patient who had been on itraconazole for fungal pneumonia developed constipation, mucositis, and granulocytopenia within one week after the first dose of vinorelbine and cisplatin, and died 12 days later. No other details were available.

MANAGEMENT: Concomitant use of vinca alkaloids with potent CYP450 3A4 and/or P-glycoprotein inhibitors should be avoided if possible. Some authorities recommend avoiding concomitant use of vinca alkaloids during and for 2 weeks after treatment with itraconazole. Otherwise, conservative dosing of the antineoplastic should be considered, and the patient closely monitored for toxicity. Based on the known half-life of vinca alkaloids (24 to 48 hours), the time course of interaction is expected to be approximately 5 to 7 days. Patients should be advised to seek medical attention if they experience symptoms that could indicate neuro- or myelotoxicity, including constipation, abdominal pain or bloating, urinary retention, paresthesia, paralysis, muscle weakness, hearing loss, seizures, erratic blood pressure changes, unusual or excessive bleeding, easy bruising, pallor, fatigue, dizziness, lightheadedness, fever, chills, and sore throat. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the antineoplastic dosage is adjusted upward to the previous dosage.

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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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