Drug Interactions between bortezomib and upadacitinib

GENERALLY AVOID: Grapefruit, grapefruit juice or supplements containing grapefruit may increase the plasma concentrations of upadacitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit. In study subjects, administration with the potent CYP450 3A4 inhibitor ketoconazole increased upadacitinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 70% and 75%, 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. Upadacitinib side effects including lymphopenia, neutropenia, anemia, serious infections, and hyperlipidemia may be increased.

MONITOR CLOSELY: Smoking during treatment with upadacitinib may increase the risk of major adverse cardiovascular events (MACE) and the risk of developing malignancies. During upadacitinib clinical studies, current or past smokers had an additional increased risk of overall malignancies. Also, upadacitinib may increase patients' risk of MACE, including myocardial infarction, stroke, and cardiovascular death.

MANAGEMENT: The manufacturer advises that concomitant use of upadacitinib with grapefruit, grapefruit juice, or supplements containing grapefruit should be avoided. Caution is advised if upadacitinib is prescribed to current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. The manufacturer recommends discontinuing upadacitinib in patients who have experienced a myocardial infarction or stroke.

GENERALLY AVOID: Data from in vitro and animal (mice) studies suggest that green tea may antagonize the cytotoxic effects of bortezomib. Polyphenols in green tea such as (-)-epigallocatechin gallate (EGCG) have been shown to block the proteasome inhibitory action of bortezomib in multiple myeloma and glioblastoma cancer cell lines. The mechanism appears to involve a direct chemical reaction between the boronic acid moiety of bortezomib and the 1,2-benzenediol groups present in certain polyphenols leading to inactivation of bortezomib. However, one group of investigators reported that no antagonism of bortezomib was observed in preclinical in vivo experiments where EGCG plasma concentrations are commensurate with dietary or supplemental intake.

MANAGEMENT: Until more data are available, it may be advisable to avoid or limit consumption of green tea and green tea products during treatment with bortezomib. The interaction has not been demonstrated for other, non-boronic acid proteasome inhibitors.