Drug Interactions between cobimetinib and Zytiga

ADJUST DOSING INTERVAL: Food may significantly increase the oral bioavailability of some formulations of abiraterone acetate. Compared to administration in the fasted state, abiraterone peak plasma concentration (Cmax) and systemic exposure (AUC) were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat; 300 calories) and approximately 17- and 10-fold higher, respectively, when it was administered with a high-fat meal (57% fat; 825 calories). Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. The safety of these increased exposures during multiple dosing has not been assessed. However, the abiraterone acetate 125 mg tablet, commonly marketed as Yonsa, was found to have an approximately 6.5-fold higher Cmax and 4.4-fold higher AUC when a single dose of 500 mg (4 tablets) was administered with a high-fat meal (56% - 60% fat, 900 - 1000 calories) compared to overnight fasting in healthy volunteers. These differences were not considered clinically significant for this formulation.

MANAGEMENT: Some formulations of abiraterone acetate must be taken on an empty stomach. No food should be consumed for at least two hours before and one hour after the abiraterone acetate dose. However, the abiraterone acetate 125 mg tablet, commonly marketed as Yonsa, can be taken with or without food. The manufacturer's product labeling should be consulted for specific guidance.

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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.

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