Drug Interactions between Reyataz and sparsentan

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of sparsentan, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. Concomitant use with potent CYP450 3A4 inhibitor itraconazole increased sparsentan peak plasma concentration (Cmax) and systemic exposure (AUC) by 25% and 174%, respectively. Increased exposure to sparsentan may increase the risk of hepatotoxicity, acute kidney injury, hyperkalemia, edema, and hypotension. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

MONITOR CLOSELY: Moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using an endothelin and angiotensin II receptor antagonist such as sparsentan. Sparsentan can promote hyperkalemia through inhibition of the renin-angiotensin-aldosterone system (RAAS). Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

Administration of a single oral dose of sparsentan 800 mg following a high-fat, high-calorie meal (1000 kcal, 50% fat), increased sparsentan AUC and Cmax by 22% and 108%, respectively. However, no clinically significant differences in sparsentan pharmacokinetics were observed following administration of a single 200 mg dose with a high-fat, high-calorie meal.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with sparsentan. Patients should receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their physician. If salt substitutes are used concurrently, regular monitoring of serum potassium levels is recommended. Patients should also be advised to seek medical attention if they experience symptoms of hyperkalemia such as weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs. Advise patients to take the daily dose of sparsentan with water prior to either the morning or evening meal, and to maintain the same dosing schedule with respect to the time of day and in relation to meals.

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ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.

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