Drug Interactions between AccessPak for HIV PEP Expanded with Viracept and lopinavir / ritonavir

ADJUST DOSE: Coadministration with nelfinavir may decrease the plasma concentrations of lopinavir, even in the presence of low-dose ritonavir as a pharmacokinetic booster. The proposed mechanism is nelfinavir induction of lopinavir metabolism via CYP450 3A4. In 13 healthy volunteers, administration of lopinavir-ritonavir (400 mg-100 mg capsule twice a day for 21 days) in combination with nelfinavir (1000 mg twice a day for 10 days) resulted in a 21% decrease in lopinavir peak plasma concentration (Cmax), a 27% decrease in systemic exposure (AUC), and a 38% decrease in trough plasma concentration (Cmin) compared to administration of lopinavir-ritonavir alone. Conversely, nelfinavir Cmin increased by 86%, and the Cmax, AUC and Cmin of its M8 metabolite increased by 2.4-fold, 3.5-fold and 7.5-fold, respectively, compared to administration of nelfinavir alone (1250 mg twice a day for 14 days). The clinical significance of these increases in terms of safety and efficacy is unknown.

MANAGEMENT: A dosage increase is recommended for lopinavir-ritonavir when used in combination with nelfinavir. For adults, the dosage should be increased to 500 mg-125 mg (two 200 mg-50 mg tablets and one 100 mg-25 mg tablet) twice daily for the tablets and 533 mg-133 mg (6.5 mL) twice daily for the oral solution. Lopinavir-ritonavir should not be administered as a once daily regimen in combination with nelfinavir. For pediatric patients 6 months to 18 years of age, the dosage should be increased to 300 mg-75 mg/m2 twice daily for the oral solution in both treatment-naive and treatment-experienced patients, not to exceed the recommended adult dosage of 533 mg-133 mg (6.5 mL) twice daily. If weight-based dosing is preferred, the recommended dosage is 13 mg-3.25 mg/kg given twice daily for patients under 15 kg and 11 mg-2.75 mg/kg given twice daily for patients 15 kg to 45 kg. Pediatric patients weighing more than 45 kg should receive the adult dosage of lopinavir-ritonavir. Please consult the manufacturer's product labeling for pediatric dosing of the tablet formulation. Lopinavir-ritonavir should not be administered in combination with nelfinavir in patients under 6 months of age due to the lack of clinical data.

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ADJUST DOSE: Coadministration with ritonavir may significantly increase the plasma concentrations of nelfinavir. The mechanism is ritonavir inhibition of CYP450 3A4 metabolism of nelfinavir. According to the nelfinavir product labeling, ritonavir (500 mg orally every 12 hours for 3 doses) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of nelfinavir (750 mg single dose) by 44% and 152%, respectively, in 10 subjects (HIV status not stated). In a study involving 18 healthy volunteers, simultaneous administration of ritonavir (400 mg single oral dose) decreased the clearance of nelfinavir (750 mg single dose) 2-fold compared to when nelfinavir was administered alone. Nelfinavir had negligible effect on the pharmacokinetics of ritonavir.

MANAGEMENT: Alteration in dosages or regimen is recommended by the manufacturer of nelfinavir during concomitant therapy with ritonavir. However, appropriate dosages for the combination, with respect to safety and efficacy, have not been established. Patients receiving the combination should be closely monitored for toxicity such as elevations in liver function tests and undue gastrointestinal disturbances, and the dosage(s) adjusted as necessary.

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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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