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

MONITOR CLOSELY: Both saquinavir and lopinavir have been associated with prolongation of the QT interval when coadministered with ritonavir as a pharmacokinetic booster. Theoretically, combining these medications may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a study of 59 healthy volunteers aged 18 to 55 years who were administered saquinavir/ritonavir at a therapeutic dosage of 1000 mg/100 mg twice daily and a supratherapeutic dosage of 1500 mg/100 mg twice daily, the maximum mean QT prolongation (QTcS; study-specific QT interval correction) on treatment day 3 was 18.9 msec for the lower dosage and 30.2 msec for the supratherapeutic dosage, compared to 12.2 msec for the active control (moxifloxacin 400 mg). The majority of subjects (89% and 80% in the therapeutic and supratherapeutic groups, respectively) had a QTcS less than 450 msec, and none had a QTc interval exceeding the potentially clinically relevant threshold of 500 msec. In a study of 39 healthy adults who were administered lopinavir-ritonavir at a therapeutic dosage of 400 mg-100 mg twice daily and a supratherapeutic dosage of 800 mg-200 mg twice daily, the maximum mean time-matched difference in QTcF interval from placebo (after baseline correction) was 5.3 msec for the lower dosage and 15.2 msec for the supratherapeutic dosage in the 12 hours postdose on treatment day 3 when exposures were approximately 1.5 and 3-fold higher, respectively, than those observed with recommended once-daily or twice-daily dosages of lopinavir-ritonavir at steady state. No subject experienced an increase in QTcF greater than 60 msec from baseline or a QTcF interval greater than 500 msec. There have been cases of QT interval prolongation and torsade de pointes arrhythmia during postmarketing use of lopinavir-ritonavir, although causality could not be established. Limited clinical data have been published regarding the effects of saquinavir in combination with lopinavir and ritonavir on the QT interval. Two cases of QT prolongation were observed in a group of 26 pediatric patients who received lopinavir/ritonavir at higher than recommended dosages (400 mg/100 mg/m2 without concomitant NNRTI and 480 mg/120 mg/m2 with concomitant NNRTI) with saquinavir mesylate added at week 4. However, both subjects had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or preexisting cardiac abnormalities.

MONITOR CLOSELY: Both saquinavir and lopinavir have been associated with prolongation of the PR interval when coadministered with ritonavir as a pharmacokinetic booster. Theoretically, combining these medications may result in additive effects and increased risk of bradycardia and heart block. In a study of 59 healthy volunteers aged 18 to 55 years, PR interval prolongation greater than 200 msec (first-degree atrioventricular block) was observed on treatment day 3 in 40% and 47% of subjects during administration of saquinavir/ritonavir at a therapeutic dosage of 1000 mg/100 mg twice daily and a supratherapeutic dosage of 1500 mg/100 mg twice daily, respectively, compared to 3% of subjects during administration of the active control (moxifloxacin) and 5% of subjects during administration of placebo. The maximum mean PR interval changes relative to the predose baseline value were 25 msec and 34 msec for the saquinavir/ritonavir therapeutic and supratherapeutic regimens, respectively, while almost no change occurred during the moxifloxacin and placebo arms. In a study of 39 healthy adults who were administered lopinavir-ritonavir at a therapeutic dosage of 400 mg-100 mg twice daily and a supratherapeutic dosage of 800 mg-200 mg twice daily, mean changes from baseline in the PR interval ranged from 11.6 to 24.4 msec in the 12 hours postdose on treatment day 3 when exposures were approximately 1.5 and 3-fold higher, respectively, than those observed with recommended once-daily or twice-daily dosages of lopinavir-ritonavir at steady state. After baseline correction, the maximum mean difference from placebo in the PR interval was 24.9 msec for the lower dosage and 31.9 msec for the supratherapeutic dosage. Maximum PR interval observed was 286 msec, and no second- or third-degree heart block occurred. There have been postmarketing reports of asymptomatic prolongation of the PR interval in some patients receiving combination antiretroviral therapy containing lopinavir-ritonavir. Second- and third-degree atrioventricular block have occurred rarely in patients with underlying structural heart disease or preexisting conduction system abnormalities and in patients receiving lopinavir-ritonavir with other drugs known to prolong the PR interval.

MANAGEMENT: The product labeling for saquinavir and lopinavir-ritonavir both recommend that these medications not be used with other agents that can prolong the QT interval. Whether they should be used with each other is unknown, but coadministration may increase the risk of QT and PR prolongation and should preferably be avoided if possible. If concomitant use is necessary, the recommended dosages are saquinavir 1000 mg twice daily and lopinavir-ritonavir 400 mg-100 mg twice daily. Once-daily dosing of lopinavir-ritonavir has not been studied for use in combination with saquinavir. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, fainting, palpitations, syncope, and/or irregular heartbeat.

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ADJUST DOSE: Coadministration with ritonavir (RTV) may significantly increase the bioavailability of saquinavir (SQV) from both the hard gelatin capsule (HGC) and soft gelatin capsule (SGC) formulations. The mechanism is RTV inhibition of CYP450 3A4 metabolism of SQV in the intestine and liver. In seven HIV+ patients stabilized on their antiretroviral regimen, addition of RTV (300 mg orally twice a day for 4 days) increased the median peak plasma concentration (Cmax) and 8-hour area under the concentration-time curve (AUC) of SQV (HGC 600 mg three times a day) by 30-fold and 58-fold, respectively, compared to baseline. In 57 healthy volunteers, escalating single doses of SQV (HGC) and RTV yielded comparable results, but increasing RTV dosages tended to produce less than proportional increases in SQV Cmax and AUC. The magnitude of the interaction is considerably less with the SGC formulation but still substantial. In individual groups of 8 healthy volunteers, various regimens of SQV (SGC 800 mg twice a day) and RTV (200 to 400 mg twice a day) for 14 days led to an approximate overall 9.6-fold increase in SQV Cmax and 20-fold increase in SQV AUC. RTV tended to reduce intersubject variability in SQV plasma levels. SQV had negligible effect on the pharmacokinetics of RTV.

MANAGEMENT: Based on the magnitude of interaction, SQV dosage should be reduced when coadministered with RTV. A regimen of (SQV HGC or SGC:RTV) 400:400 mg or 1000:100 mg twice daily is usually recommended based on their convenience and favorable safety-to-efficacy profile. Limited data suggest that dosages of 1200 to 2000:100 mg once daily may also be feasible and warrant further investigation. Patients receiving the combination should be closely monitored for toxicity including elevations in liver function tests and neutropenia.

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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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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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