Drug Interaction Report

GENERALLY AVOID: Coadministration with potent and moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of cobimetinib, which is primarily metabolized by the isoenzyme. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that cobimetinib exposures would decrease by 83% when coadministered with a potent CYP450 3A4 inducer and by 73% when coadministered with a moderate CYP450 3A4 inducer. The therapeutic efficacy of cobimetinib may be reduced.

MANAGEMENT: Concomitant use of cobimetinib with potent or moderate CYP450 3A4 inducers should generally be avoided.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme, such as cobimetinib. However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of cobimetinib. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.