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

MONITOR: Coadministration with ritonavir may decrease the plasma concentrations of the benzimidazoles, albendazole and mebendazole, as well as the active metabolite of albendazole, albendazole sulfoxide. The precise mechanism has not been established, but may be related to the induction of CYP450 1A2, CYP450 2C9, and/or uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) by ritonavir following chronic administration. A pharmacokinetic study evaluating the effects of a single dose of either albendazole (400 mg) (n=8) or mebendazole (1000 mg) (n=8) administered with ritonavir (200 mg twice daily for 8 days) in healthy, nonsmoking male Caucasian subjects reported a significant reduction in the systemic exposure (AUC) and maximum plasma concentration (Cmax) of both albendazole and mebendazole. Specifically, mean AUC decreased to 27% and 43% of baseline for albendazole and mebendazole, respectively, and Cmax decreased to 26% and 41% of baseline, respectively. Albendazole sulfoxide AUC and Cmax were reduced to 41% and 52% of baseline, respectively. By contrast, pharmacokinetic parameters for albendazole, mebendazole, and albendazole sulfoxide were not significantly altered following administration of ritonavir for 2 doses only. The clinical relevance of the interaction observed following chronic ritonavir administration is unknown, since therapeutic ranges to optimize efficacy have not been established for either albendazole or mebendazole. Clinical impact is expected to be minimal in the treatment of intestinal infections, but may be increased when albendazole or mebendazole is used for systemic helminthic diseases.

MANAGEMENT: Caution and monitoring for altered clinical efficacy are recommended if albendazole or mebendazole is used in combination with ritonavir in patients being treated for systemic helminthic infections. Dose adjustments or alternative treatments may be required if an interaction is suspected.

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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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