Drug Interactions between cyclosporine and Pyrukynd

GENERALLY AVOID: Theoretically, the coadministration with grapefruit juice may increase the plasma concentrations of mitapivat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. 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. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid or limit consumption of grapefruit or grapefruit juice during therapy with mitapivat if possible. If concomitant use is unavoidable, close monitoring of hemoglobin levels and for the development of adverse effects such as atrial fibrillation, gastroenteritis, rib fracture, musculoskeletal pain, arthralgia, increased urate levels, and in males, for decreased estrone and estradiol levels, is recommended. The product labeling should be consulted for dose adjustments of mitapivat in the event of the development of adverse reaction or hemoglobin levels above normal.

GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.