Drug Interactions between mercaptopurine and voclosporin

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of voclosporin. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because voclosporin prolongs the QT interval in a dose-dependent manner, high plasma levels of voclosporin may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes. In drug interaction studies, coadministration with multiple doses of moderate CYP450 3A4 inhibitors fluconazole or diltiazem is predicted to increase the peak plasma concentration (Cmax) and the area under the 12-hour plasma concentration-time curve (AUC 0-12) of voclosporin by approximately 2- and 3-fold respectively. 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In addition, moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using voclosporin, which has been reported with the use of voclosporin. Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

ADJUST DOSING INTERVAL: Consumption of food can decrease the rate and extent of gastrointestinal absorption of voclosporin. When administered with either low- or high-fat meals, the peak plasma concentration (Cmax) of voclosporin decreased by 29% to 53% and systemic exposure (AUC) decreased by 15% to 25%.

MANAGEMENT: Patients receiving voclosporin therapy should be advised to avoid consumption of grapefruit or grapefruit juice. Voclosporin therapy should be administered at least 1 hour before or 2 hours after meals. Patients should also receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their doctor. 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.

ADJUST DOSING INTERVAL: The oral bioavailability of mercaptopurine (6-MP) is highly variable and may be affected by administration with food or dairy products. The mechanism by which food may impact the absorption of 6-MP has not been fully established, but cow's milk specifically has been found to contain a high concentration of xanthine oxidase, the enzyme responsible for first-pass metabolism of 6-MP to the inactive metabolite 6-thiouric acid. Incubation with cow's milk at 37 C induced a 30% catabolism of 6-MP within 30 minutes in one investigation. However, food or dairy intake with 6-MP in study patients has yielded variable results. In a study conducted in 17 children with acute lymphoblastic leukemia (ALL), oral 6-MP 75 mg/m2 administered 15 minutes after a standardized breakfast including 250 mL of milk resulted in a prolonged Tmax and a lower Cmax and AUC compared with 6-MP administration in the fasting state (mean Tmax: 2.3 hours vs. 1.2 hours; mean Cmax: 0.63 uM vs. 0.98 uM; mean AUC: 105 uM vs. 143 uM, respectively). In a different study, oral 6-MP 31.2 to 81.1 mg/m2 administered to 7 subjects with ALL 15 minutes after a standard breakfast consisting of orange juice, cereal, and toast also trended towards longer Tmax and lower Cmax values compared to 6-MP administration after an overnight fast, although the differences were not statistically significant. Two subjects had blood samples that were all below the limit of detection (20 ng/mL) following administration in the fed state. Likewise, a study of 15 pediatric patients reported non-significant 20% to 22% decreases in the Cmax and AUC of 6-MP when administered after a standardized breakfast containing both milk and cheese compared to administration after fasting, but in contrast to the two earlier studies, Tmax was decreased from 1.8 to 1.1 hours. Another study of 10 children with ALL or non-Hodgkin's lymphoma given an average oral 6-MP dose of 63 mg/m2 revealed substantial interpatient variations in the effect of food intake on 6-MP plasma levels, with Cmax changes ranging from 67% decrease to 81% increase and AUC changes ranging from 53% decrease to 86% increase relative to administration following fasting. Collectively for the group, however, there was no statistically significant difference in mean Tmax, Cmax, or AUC between the fed and fasting states. In this study, patients were fed what they normally ate at home rather than a standardized breakfast, which may have contributed to the inconsistent results. The clinical significance of the data and observations from these studies has not been determined. An interaction with milk was suspected in a four-year-old male with ALL who experienced persistent elevations of peripheral blood counts during maintenance with 6-MP and methotrexate despite increasing doses of 6-MP up to 160% of the calculated dosage for his body surface area (75 mg/m2). Cessation of concomitant milk ingestion allowed for the 6-MP dosage to return to 75 mg/m2 and resulted in control of peripheral blood counts within a week. Other data do not support a clinically relevant interaction with food or dairy products. In a prospective study of 441 patients aged 2 to 20 years receiving 6-MP for ALL maintenance, investigators found no significant association between relapse risk and 6-MP ingestion habits including administration with food versus never with food and administration with milk/dairy versus never with milk/dairy. Among the 56.2% of patients who were considered adherent by the study, there was also no significant association between red cell thioguanine nucleotide (active metabolite) levels and taking 6-MP with food versus without or taking with milk/dairy versus without. However, taking 6-MP with milk/dairy was associated with a 1.9-fold increased risk for nonadherence. These results suggest that taking 6-MP with food or milk/dairy products may not influence clinical outcome but may hinder patient adherence. Poor 6-MP adherence has been associated with an increased risk of childhood ALL relapse.

MANAGEMENT: To minimize variability in absorption and systemic exposure, the timing of mercaptopurine administration should be standardized in relation to food intake (i.e., always with food or always on an empty stomach). Some authorities suggest avoiding concomitant administration with milk or dairy products, although the clinical relevance of their effects on mercaptopurine bioavailability has not been established. As a precaution, patients may consider taking mercaptopurine at least 1 hour before or 2 hours after milk or dairy ingestion if they are able to do so without compromising treatment adherence.