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

ADJUST DOSING INTERVAL: Coadministration of lopinavir-ritonavir and phenytoin may result in decreased plasma concentrations of both lopinavir and phenytoin. The proposed mechanism involves phenytoin induction of lopinavir metabolism via CYP450 3A4 and ritonavir induction of phenytoin metabolism via CYP450 2C9 and 2C19. In 12 healthy volunteers, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) with phenytoin (300 mg once daily on days 11 thru 22) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 24%, 33% and 46%, respectively. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant. In a different arm of the same study, Cmax, AUC and Cmin of phenytoin decreased by 28%, 31% and 34%, respectively, when phenytoin (300 mg once daily for 22 days) was coadministered with lopinavir-ritonavir (400 mg-100 mg twice daily on days 12 thru 22) in 8 healthy subjects.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if lopinavir-ritonavir is prescribed with phenytoin. Once-daily administration of lopinavir-ritonavir should be avoided when used concomitantly with phenytoin. An increase in the dosage of lopinavir-ritonavir may be necessary, although dosage adjustment has not been evaluated in clinical studies. Close clinical and laboratory monitoring of antiretroviral response is, therefore, recommended. Additionally, the potential for reduced therapeutic effects of phenytoin should be considered during coadministration with lopinavir-ritonavir. Phenytoin serum levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly.

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GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) may decrease the oral bioavailability and plasma concentrations of tenofovir alafenamide (TAF), which is a substrate of the efflux transporter. In 26 healthy study subjects, administration of TAF (25 mg once daily) with the P-gp inducer carbamazepine (300 mg twice daily) decreased TAF plasma concentration (Cmax) and systemic exposure (AUC) by an average of 57% and 55%, respectively, compared to TAF administered alone. It is not known if, and to what extent, tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, may interact with P-gp inducers. The interaction has not been studied with TDF, and no information is found in the labeling of various products containing TDF, although it has been reported to be a P-gp substrate also.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of tenofovir alafenamide fumarate with P-gp inducers is not recommended. Whether this also applies to tenofovir disoproxil fumarate has not been established.

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MONITOR: Coadministration of ritonavir and phenytoin may result in decreased plasma concentrations of both drugs. The proposed mechanism involves ritonavir induction of phenytoin metabolism via CYP450 2C9 and, conversely, phenytoin induction of ritonavir metabolism via CYP450 3A4. Data are limited. In one case report, serum phenytoin levels in a patient receiving carbamazepine (1200 mg/day), phenytoin (500 mg/day), and phenobarbital (250 mg/day) declined 30% following initiation of antiretroviral therapy containing ritonavir (300 mg twice a day). In another case, a patient receiving carbamazepine (600 mg/day) and phenytoin (400 mg/day) was started on ritonavir (600 mg twice daily) with no apparent change in serum phenytoin levels. In a pharmacokinetic study of 8 healthy volunteers, administration of phenytoin (300 mg once daily for 22 days) in combination with lopinavir-ritonavir (400 mg-100 mg twice a day on days 12 thru 22) decreased phenytoin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 28%, 31% and 34%, respectively, compared to administration of phenytoin alone. In a different arm of the same study, Cmax, AUC and Cmin of lopinavir decreased by 24%, 33% and 46%, respectively, when lopinavir-ritonavir (400 mg-100 mg twice a day for 22 days) was coadministered with phenytoin (300 mg once daily on days 11 through 22) in 12 healthy subjects. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant.

MANAGEMENT: The potential for reduced therapeutic effects of phenytoin should be considered during coadministration with ritonavir. Phenytoin serum levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of ritonavir in patients who are stabilized on their anticonvulsant regimen. In addition, it may be necessary to monitor patients for potentially reduced antiretroviral response due to decreased plasma levels of ritonavir and other antiretroviral agents induced by phenytoin.

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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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