Drug Interactions between enfortumab vedotin and larotrectinib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and effects of unconjugated monomethyl auristatin E (MMAE). Enfortumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE, a microtubule-disrupting agent believed to induce cell cycle arrest and apoptosis, via proteolytic cleavage. MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4. According to physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumab vedotin with ketoconazole, a dual P-gp and strong CYP450 3A4 inhibitor, is predicted to increase unconjugated MMAE peak plasma concentration (Cmax) by 15% and systemic exposure (AUC) by 38%, with no change in ADC exposure. In one case report, a 70-year-old man on stable doses of raltegravir and the CYP450 3A4 inhibitors darunavir and ritonavir, experienced severe toxicity after receiving 2 infusions of enfortumab vedotin (1.25 mg/kg on days 1 and 8 of his 28-day cycle). He was hospitalized with a severe generalized pruritic rash, thrush, mucositis, anorexia, diarrhea, acute kidney injury, and pancytopenia. Enfortumab vedotin was withheld and the patient returned to baseline after being treated with supportive measures. About a year later, he was rechallenged with enfortumab vedotin while on an antiretroviral regimen consisting of dolutegravir, doravirine, and valacyclovir. He was able to tolerate a reduced dose of 1 mg/kg, with mild expected toxicity including skin blisters and peripheral neuropathy. It is not known if, and to what extent, enfortumab vedotin may interact with less potent CYP450 3A4 inhibitors.

MANAGEMENT: Patients should be closely monitored for development or exacerbation of toxicities including, but not limited to skin reactions (maculopapular rash, pruritus, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmar-plantar erythrodysesthesia, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)); hyperglycemia (including diabetic ketoacidosis); pneumonitis or interstitial lung disease; peripheral neuropathy; and ocular disorders (dry eyes, keratitis, blurred vision, limbal stem cell deficiency). Refer to the product labeling for dose adjustment or discontinuation of therapy recommendations depending on the severity or Grade of the adverse reactions, should they occur.