Bortezomib and Alcohol/Food Interactions

GENERALLY AVOID: Preliminary data suggest that ascorbic acid may diminish the antitumor effects of bortezomib when taken simultaneously. In vitro, ascorbic acid has been shown to inhibit several biologic activities of bortezomib, including induction of apoptosis and G2-M cell cycle arrest and inhibition of proteasome activity, presumably by forming a complex with bortezomib that is both inactive and has poor membrane permeability into cells. A group of investigators showed that plasma from healthy volunteers taking 1 gram of vitamin C per day reduced bortezomib-induced multiple myeloma cell death in vitro. Using a mouse model of human multiple myeloma, they also found that oral vitamin C (40 mg/kg/day) blocked the inhibition of tumor cell growth induced by bortezomib (0.1 mg/kg twice a week for 4 weeks) in immunocompromised mice. The interaction has also been observed in an endometrial carcinoma cell line. In contrast, no effect of ascorbic acid (at plasma concentrations commensurate with human supplemental intake) on bortezomib activity was found in immunocompromised mice bearing CWR22 human prostate xenograft tumors. In light of the fact that vitamin C may protect normal cells from bortezomib toxicity, more studies are needed to further clarify the clinical significance of these findings.

MANAGEMENT: Until more data are available, it may be advisable to avoid taking supplements containing ascorbic acid during bortezomib therapy, or at least on bortezomib treatment days.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

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.