Evaluation of the Effect of Cendakimab on the Pharmacokinetics of CYP Probe Drugs in Patients With Eosinophilic Esophagitis

Abstract

Cendakimab is a humanized monoclonal antibody that inhibits interleukin‐13 binding to its receptors. Although not expected to share clearance pathways with small molecules, its use in eosinophilic esophagitis, a type 2 inflammatory disease, may indirectly affect cytochrome P450 activity by modulating cytokine signaling affecting certain cytochrome P450 enzymes. This open‐label, single‐sequence study evaluated the pharmacokinetics of cytochrome P450 substrates in adults with active eosinophilic esophagitis, evidenced by a peak eosinophil count of ≥ 15 per high‐power field in esophageal biopsies and clinical symptoms of esophageal dysfunction, before and after 16 weeks of cendakimab treatment. Patients received a cocktail of probe substrates (caffeine 200 mg, warfarin 10 mg + vitamin K 10 mg, omeprazole 40 mg, dextromethorphan 30 mg, midazolam 5 mg) for cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A in two sequential periods, separated by 16 weeks of cendakimab treatment. Blood samples were analyzed to assess pharmacokinetics. Sixteen patients were treated; 15 completed the study. Exposures (AUC and Cmax) of caffeine, S‐warfarin, midazolam, and omeprazole were comparable before and after treatment. Dextromethorphan exposure showed no clinically meaningful change, although interpretation is limited by small sample size. Cendakimab was well tolerated. All adverse events were mild to moderate, with no serious adverse events, deaths or discontinuations from adverse events. No clinically relevant changes in laboratory tests, vital signs, or electrocardiograms were observed. Cendakimab had no clinically meaningful effects on cytochrome P450 enzyme activities and was generally safe and well tolerated with or without probe substrates in adults with active eosinophilic esophagitis.