Drug Interactions between belumosudil and Tazverik

GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during tazemetostat therapy may significantly increase the plasma concentrations of tazemetostat. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of tazemetostat by certain compounds in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). According to the product labeling, coadministration of tazemetostat (400 mg twice daily) with the moderate CYP450 3A4 inhibitor fluconazole increased the tazemetostat steady state exposure (AUC 0 to 8 hours) by 3.1-fold and peak plasma concentration by 2.3-fold. 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. Clinically, this interaction may result in an increased risk of the frequency or severity of adverse reactions due to tazemetostat such as hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.

MANAGEMENT: The manufacturer advises that patients treated with tazemetostat should avoid consumption of grapefruit or grapefruit juice.

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ADJUST DOSING INTERVAL: Administration with food increases the oral bioavailability of belumosudil. The mechanism has not been described. Administration of belumosudil (200 mg single oral dose) in healthy subjects, with a fatty and calorie-rich meal (approximately half of the calories were contained in the fat) increased the mean belumosudil peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 120% and 100%, respectively, compared to administration under fasting conditions. The time to reach peak concentration (Tmax) was delayed by 30 minutes. Administration of oral belumosudil 200 mg once daily with food in patients with chronic graft-versus-host disease (chronic GVHD) lead to steady-state concentrations of the drug with an accumulation ration of 1.4.

MANAGEMENT: To ensure maximal oral absorption, belumosudil should be administered with a meal, every day at the same time.

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