Refractory Diabetic Ketoacidosis Associated with Enfortumab Vedotin

Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) approved for metastatic urothelial carcinoma, is increasingly recognized to cause severe hyperglycemia and diabetic ketoacidosis (DKA). However, optimal management of EV-associated refractory DKA remains undefined. We describe a 57-year-old man receiving EV and pembrolizumab who developed profound insulin-resistant DKA that persisted despite standard therapy. EV is composed of a nectin-4-targeted monoclonal antibody linked to the cytotoxic agent monomethyl auristatin E (MMAE), which is the primary cause of systemic toxicity. Systemic elimination of MMAE is via metabolism by cytochrome P450 (CYP) 3A4 and biliary/fecal excretion. Tissue exposure is limited via P-glycoprotein efflux pump. Therefore, in the setting of refractory DKA, a pharmacologic enzyme induction was initiated to mitigate further MMAE-induced injury. Following initiation of induction alongside continued insulin therapy, resolution of ketoacidosis occurred within 46 hours. This case illustrates a pharmacokinetic-informed approach to EV-associated refractory DKA and highlights how understanding drug metabolism may improve therapeutic outcomes when conventional therapy is insufficient.