Evaluation of Clinical Cardiac Safety of Itacitinib, a JAK1 Inhibitor, in Healthy Participants.

Itacitinib is a JAK1-selective inhibitor in phase 3 development in graft-versus-host disease. A post hoc electrocardiogram (ECG) analysis and a plasma concentration-QTc (C-QTc) analysis were performed to assess cardiac safety using data from the first-in-human itacitinib study. The study included 2 cohorts of 12 healthy participants each in an interleaving dosing design with single doses of 10-300 mg or placebo; 500 and 1000 mg doses were subsequently added with 12 participants randomized to itacitinib or placebo. Continuous Holter recordings were collected from 1 hour predose to 8 hours postdose on each dosing day, and ECG intervals were blindly extracted to match timed pharmacokinetic samples. Data showed no hysteresis, and a prespecified linear mixed-effects C-QTc model was used with change-from-baseline QTcF (QT interval corrected for heart rate by Fridericia's method) as the dependent variable, plasma itacitinib concentrations and centered baseline QTcF as continuous covariates, treatment and time as categorical factors, and a random intercept per participant. The estimated slope of the C-QTc relationship was not significantly different from zero: 0.0002 milliseconds per nM (90%CI, -0.00019 to 0.00054 milliseconds). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. A QTc effect exceeding the threshold of concern (10 milliseconds) can be excluded for itacitinib plasma concentrations up to ∼13 000 nM (∼7200 ng/mL), which is well above the maximum concentration expected with the highest proposed therapeutic dose of itacitinib either with concomitant use of cytochrome P450 3A4 inhibitors or in patients with impaired hepatic function.

RCT Entities:   Population Interventions Outcomes