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Drug Interactions between bortezomib and ivacaftor / lumacaftor

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

bortezomib lumacaftor

Applies to: bortezomib and ivacaftor / lumacaftor

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations and pharmacologic effects of bortezomib, which is primarily metabolized by the isoenzyme with secondary contribution from CYP450 2C19. In a study of patients with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma treated with intravenous bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11 of each 21-day cycle) for 3 cycles, six patients who were coadministered the potent CYP450 3A4 inducer rifampin (600 mg once daily on days 4 to 10 of cycle 3) had an approximately 23% decrease in bortezomib peak plasma concentration (Cmax) and 45% decrease in systemic exposure (AUC) compared to 12 patients treated with bortezomib alone. Because the study was not designed to exert the maximum effect of rifampin on bortezomib pharmacokinetics, greater decreases may be possible. In the same study, seven patients who were coadministered the weaker CYP450 3A4 inducer dexamethasone (40 mg once daily on days 1 to 4 and 9 to 12 of cycle 3) did not demonstrate significant changes in the pharmacokinetics of bortezomib compared to patients administered bortezomib alone. In a phase I trial to determine the dose-limiting toxicities and maximum tolerated dose (MTD) of bortezomib in patients with recurrent high-grade gliomas, patients who received concomitant enzyme-inducing antiepileptic drugs (primarily phenytoin, but also carbamazepine, oxcarbazepine, phenobarbital, and primidone) were found to tolerate a higher dosage of bortezomib compared to those who either did not receive antiepileptic medications or received ones that did not significantly induce hepatic microsomal enzymes. Bortezomib doses were escalated to 2.5 mg/m2 without reaching the MTD in the former group, whereas MTD was found to be 1.7 mg/m2 in the latter group. Moreover, maximum proteasome inhibition was reached at a higher dosage of bortezomib in the former group relative to the latter group. Although pharmacokinetics of bortezomib were not examined in the trial, these results suggest enhanced clearance of bortezomib in the presence of enzyme-inducing antiepileptic drugs.

MANAGEMENT: Given the potential for diminished pharmacologic effects of bortezomib in the presence of potent CYP450 3A4 inducers, concomitant use is not recommended.

References

  1. (2003) "Product Information. Velcade (bortezomib)." Millennium Pharmaceuticals Inc
  2. Uttamsingh V, Lu C, Miwa GT, Gan LS (2005) "Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4 to the hepatic metabolism of teh protosome inhibitor bortezomib." Drug Metab Dispos, 33, p. 1723-8
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  4. Pekol T, Daniels JS, Labutti J, et al. (2005) "Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites." Drug Metab Dispos, 33, p. 771-7
  5. Hellmann A, Rule S, Walewski J, et al. (2011) "Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or Non-Hodgkin's lymphoma." Clin Pharmacokinet, 50, p. 781-91
  6. Phuphanich S, Supko JG, Carson KA, et al. (2010) "Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma." J Neurooncol, 100, p. 95-103
View all 6 references

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Drug and food interactions

Moderate

bortezomib food

Applies to: bortezomib

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.

References

  1. Bannerman B, Xu L, Jones M, et al. (2011) "Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea." Cancer Chemother Pharmacol, 68, p. 1145-54
  2. Golden EB, Lam PY, Kardosh A, et al. (2009) "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid–based proteasome inhibitors." Blood, 113, p. 5927-37
  3. Jia L, Liu FT (2013) "Why bortezomib cannot go with 'green'?" Cancer Biol Med, 10, p. 206-13

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Moderate

ivacaftor food

Applies to: ivacaftor / lumacaftor

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.

References

  1. (2012) "Product Information. Kalydeco (ivacaftor)." Vertex Pharmaceuticals
  2. (2015) "Product Information. Orkambi (ivacaftor-lumacaftor)." Vertex Pharmaceuticals
  3. (2022) "Product Information. Symdeko (ivacaftor-tezacaftor)." Vertex Pharmaceuticals
  4. (2019) "Product Information. Trikafta (elexacaftor/ivacaftor/tezacaftor)." Vertex Pharmaceuticals
View all 4 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

See also

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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