Drug Interactions between regorafenib and Sulfimycin

ADJUST DOSING INTERVAL: Food may variably affect the bioavailability of different oral formulations and salt forms of erythromycin. The individual product package labeling should be consulted regarding the appropriate time of administration in relation to food ingestion. Grapefruit juice may increase the plasma concentrations of orally administered erythromycin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In an open-label, crossover study consisting of six healthy subjects, the coadministration with double-strength grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single dose of erythromycin (400 mg) by 52% and 49%, respectively, compared to water. The half-life was not affected. The clinical significance of this potential interaction is unknown.

MANAGEMENT: In general, optimal serum levels are achieved when erythromycin is taken in the fasting state, one-half to two hours before meals. However, some erythromycin products may be taken without regard to meals.

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ADJUST DOSING INTERVAL: Depending on the amount of fat, food may enhance the oral bioavailability of both regorafenib and its active metabolites, M-2 and M-5. In 24 healthy male subjects, administration of regorafenib with a high-fat meal (945 calories; 54.6 g fat) increased the mean systemic exposure (AUC) of regorafenib by 48% but decreased the mean AUC of M-2 and M-5 by 20% and 51%, respectively, compared to administration under the fasted state. In contrast, administration with a low-fat meal (319 calories; 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively, compared to administration during fasting.

GENERALLY AVOID: Coadministration with grapefruit juice may alter the pharmacokinetics of regorafenib and its active metabolites. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied specifically with grapefruit juice, but has been reported with the potent CYP450 3A4 inhibitor, ketoconazole. In 18 healthy male study subjects, administration of a single 160 mg dose of regorafenib on day 5 of treatment with ketoconazole (400 mg daily for 18 days) resulted in a 33% increase in mean regorafenib systemic exposure (AUC) compared to administration of regorafenib alone. Additionally, there was a 93% decrease each in the mean AUC of the M-2 and M-5 metabolites. Both have been shown to have similar in vitro pharmacological activity and steady-state concentrations as regorafenib, thus the net clinical effect of these pharmacokinetic changes is unknown.

MANAGEMENT: To ensure optimal oral absorption, regorafenib should be administered with a low-fat breakfast that contains less than 30% fat. Examples of a low-fat breakfast include: 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, plus 8 ounces of skim milk (319 calories; 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories; 2 g fat). Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with regorafenib.

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Ethanol, when combined with erythromycin, may delay absorption and therefore the clinical effects of the antibiotic. The mechanism appears to be due to slowed gastric emptying by ethanol. Data is available only for erythromycin ethylsuccinate. Patients should be advised to avoid ethanol while taking erythromycin salts.

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