Drug Interactions between emtricitabine / nelfinavir / tenofovir and Fortovase

GENERALLY AVOID: Coadministration with nelfinavir may significantly increase the bioavailability of saquinavir from both the hard gelatin capsule (HGC) and soft gelatin capsule (SGC) formulations. The mechanism is nelfinavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of saquinavir. In six HIV+ patients stabilized on their antiretroviral regimen, addition of nelfinavir (750 mg orally three times a day for 2 days) resulted in mean peak plasma concentration (Cmax) and 8-hour area under the concentration-time curve (AUC) for saquinavir (HGC 600 mg three times a day) that were approximately five times those at baseline. In 14 HIV+ patients, coadministration of nelfinavir (750 mg orally three times a day for 4 days) and saquinavir (SGC 1200 mg single dose) yielded increases in saquinavir Cmax and AUC of 179% and 392%, respectively, according to the product labelings. In 18 healthy volunteers, simultaneous administration of nelfinavir (750 mg single oral dose) decreased the clearance of saquinavir (SGC 800 mg single dose) 10-fold compared to when saquinavir was administered alone. Saquinavir had negligible effect on the pharmacokinetics of nelfinavir. In addition, in 12 HIV+ patients administered multiple doses of saquinavir-ritonavir (1000 mg-100 mg twice a day) with nelfinavir (1250 mg twice a day), there were negligible increases in the AUC and Cmax of saquinavir of 13% and 9%, respectively. There were also negligible changes in the AUC and Cmax of nelfinavir, with a reduction of 6% and 5%, respectively.

MANAGEMENT: Due to a high degree of interpatient variability in saquinavir bioavailability, the interaction with nelfinavir may benefit some patients while exposing others to excessively high saquinavir levels and potential toxicity. The combination of ritonavir-boosted saquinavir and nelfinavir is generally not recommended; 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, including elevations in liver function tests and serum creatinine phosphokinase and neutropenia, 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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