Drug Interactions between emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and enfortumab vedotin

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.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.