Drug Interaction Report

MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 or dual P-glycoprotein (P-gp) and strong CYP450 3A4 inhibitors 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 as well as being a substrate of P-gp. 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.

MANAGEMENT: Caution is advised when enfortumab vedotin is used concomitantly with either potent CYP450 3A4 inhibitors or dual P-glycoprotein (P-gp) and strong CYP450 3A4 inhibitors. 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.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of telaprevir. When given with a meal containing 533 kcal and 21 g fat, telaprevir systemic exposure (AUC) increased by 237% compared to administration under fasting conditions. The type of meal also affects the exposure to telaprevir. Relative to fasting, telaprevir AUC increased by approximately 117% with a low-fat meal (249 kcal; 3.6 g fat) and 330% with a high-fat meal (928 kcal; 56 g fat). In Phase 3 clinical trials, telaprevir doses were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat.

MANAGEMENT: Telaprevir should be administered with food containing approximately 20 grams of fat. Patients should be advised that the fat content of the meal or snack is critical to the absorption of telaprevir. Food taken with telaprevir should be ingested within 30 minutes prior to each dose. Examples of some foods that could be taken with telaprevir include: bagel with cream cheese; half cup of nuts; 3 tablespoons of peanut butter; 1 cup of ice cream; 2 ounces of American or cheddar cheese; 2 ounces of potato chips; or half cup of trail mix.