Drug Interaction Report

MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of unconjugated monomethyl auristatin E (MMAE), the anti-mitotic and cytotoxic component of brentuximab vedotin. Brentuximab vedotin is an antibody-drug conjugate (ADC) that releases MMAE via proteolytic cleavage, and MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4. When brentuximab vedotin was administered with the potent CYP450 3A4 inhibitor ketoconazole, MMAE peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 25% and 34%, respectively, with no change in ADC exposure. Using a model-based approach to account for the fact that MMAE exposures are decreased after multiple doses by 20% to 50% compared to the first dose, the adjusted increase in MMAE AUC by ketoconazole is predicted to be 73%.

MANAGEMENT: Caution is advised when brentuximab vedotin is used concomitantly with potent CYP450 3A4 inhibitors. Close monitoring for adverse effects including neutropenia, infection, peripheral neuropathy, hepatotoxicity, pulmonary toxicity and hyperglycemia is recommended, and the dosing of brentuximab vedotin adjusted or withheld as necessary in accordance with the product labeling.

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MONITOR: Coadministration of brentuximab vedotin with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Serious cases of hepatotoxicity, some fatal, have occurred in patients treated with brentuximab vedotin. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and typically occurred after the first dose or after a rechallenge. Preexisting liver disease and elevated baseline liver enzymes may also increase the risk.

MANAGEMENT: The risk of hepatic injury should be considered when brentuximab vedotin is used with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Liver enzymes and bilirubin should be measured before and during treatment, especially in patients with underlying hepatic disease or marked baseline transaminase elevations. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dosage, or discontinuation of brentuximab vedotin in accordance with the product labeling.

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ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.

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