230 Dosing Strategy for Itacitinib, a Selective JAK1 Inhibitor, for the Treatment of Ulcerative Colitis

INTRODUCTION: Itacitinib is a JAK1 inhibitor currently under development for oncologic and auto-immune diseases. Itacitinib is delivered as a sustained release formulation with 27.1% of the dose eliminated as unchanged itacitinib in the feces. A clinical and an ex vivo study were conducted to understand colonic disposition, important for ulcerative colitis (UC). METHODS: Clinical study: Itacitinib concentrations in plasma and feces (colonic surrogate) were determined following a single 25 mg oral dose. Itacitinib concentrations in plasma following a single 100 mg dose were also determined in a separate study. Ex vivo study: Colon tissue samples from healthy and UC subjects (2/group) were mounted on a vertical Ussing diffusion chamber. 14 C-Itacitnib was applied to the apical side of the chamber at 100 and 1000 nM and incubated for 1 h. Samples were collected from the donor and receiver sides for determination of itacitinib concentration. The colonic tissue was snap frozen for quantitative autoradiography. RESULTS: Following a single 25 mg dose of itacitinib, 8/12 patients had fecal concentrations that exceeded the in vitro IC 50 for JAK1 inhibition. Systemic concentrations were below the IC 50 for JAK1 inhibition in whole blood at both doses evaluated, mean (SD) Cmax = 18.9 (7.46) nM for 25 mg and 84.4 (45.8) nM for 100 mg. Ex vivo, no itacitinib related radioactivity was detected from the receiver side. Itacitinib penetrated into the mucosal layer and, to a lesser extent, submucosal layer in a concentration dependent manner. CONCLUSION: A dose range of 25 mg BID to 100 mg QD is recommended for study in UC patients to maximize colonic exposure while minimizing the potential for systemic exposure.