Drug Interactions between brentuximab and nirogacestat

MONITOR: Coadministration with potent CYP450 3A4 inhibitors or P-glycoprotein (P-gp) inhibitors may increase the plasma concentrations of monomethyl auristatin E (MMAE), the microtubule-disrupting component of brentuximab vedotin. MMAE is primarily metabolized by CYP450 3A4 and has been found in vitro to be a substrate of the P-gp efflux transporter. In study subjects, administration of brentuximab vedotin with the potent CYP450 3A4 and P-gp inhibitor ketoconazole resulted in an approximately 34% increase in MMAE systemic exposure (AUC).

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: Caution is advised when brentuximab is used with potent CYP450 3A4 inhibitors (e.g., azole antifungal agents, clarithromycin, erythromycin, nefazodone, ritonavir, telithromycin) or P-gp inhibitors (e.g., protein kinase inhibitors, abiraterone, amiodarone, azithromycin, cyclosporine, dronedarone, ivacaftor) that are also potentially hepatotoxic. Close monitoring for adverse effects including neutropenia, infection, peripheral neuropathy, and hepatotoxicity is recommended. 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.