Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and eluxadoline

ADJUST DOSE: Coadministration with inhibitors of organic anion transporting polypeptide (OATP) 1B1 may significantly increase the plasma concentrations of eluxadoline. Based on available data, inhibition of OATP1B1-mediated hepatic uptake appears to reduce both the hepatic first-pass extraction and systemic biliary clearance of eluxadoline. In 30 healthy volunteers, administration of a single 100 mg dose of eluxadoline with a single 600 mg dose of cyclosporine, a known OATP1B1 inhibitor, increased eluxadoline peak plasma concentration (Cmax) and systemic exposure (AUC) by 6.2- and 4.4-fold, respectively, compared to administration of eluxadoline alone. Adverse events were reported in 6 study subjects during coadministration of eluxadoline with cyclosporine and in 2 subjects during administration of eluxadoline alone.

MANAGEMENT: The recommended dosage of eluxadoline is 75 mg twice daily when used with OATP1B1 inhibitors. Patients should be monitored for adverse effects such as sedation, nausea, vomiting, constipation, abdominal pain, liver enzyme elevations, and pancreatitis.

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ADJUST DOSE: Coadministration with inhibitors of organic anion transporting polypeptide (OATP) 1B1 may significantly increase the plasma concentrations of eluxadoline. Based on available data, inhibition of OATP1B1-mediated hepatic uptake appears to reduce both the hepatic first-pass extraction and systemic biliary clearance of eluxadoline. In 30 healthy volunteers, administration of a single 100 mg dose of eluxadoline with a single 600 mg dose of cyclosporine, a known OATP1B1 inhibitor, increased eluxadoline peak plasma concentration (Cmax) and systemic exposure (AUC) by 6.2- and 4.4-fold, respectively, compared to administration of eluxadoline alone. Adverse events were reported in 6 study subjects during coadministration of eluxadoline with cyclosporine and in 2 subjects during administration of eluxadoline alone.

MANAGEMENT: The recommended dosage of eluxadoline is 75 mg twice daily when used with OATP1B1 inhibitors. Patients should be monitored for adverse effects such as sedation, nausea, vomiting, constipation, abdominal pain, liver enzyme elevations, and pancreatitis.

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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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