Pacritinib Impact on QT Interval: Results of a Thorough QT Study and Post Hoc Analysis of Prospective Clinical Trial Data

Pacritinib, an inhibitor of JAK2/IRAK1/ACVR1 that is devoid of JAK1 activity, approved for treating myelofibrosis in patients with severe thrombocytopenia, carries a label warning for QT interval prolongation. To evaluate the cardiac safety of pacritinib, a randomized, placebo‐ and active‐controlled, single‐dose thorough QT (TQT) study was conducted in healthy subjects, and a dose‐finding study (PAC203) was conducted in patients with myelofibrosis. In the TQT study, 42 subjects received single doses of pacritinib 400 mg, moxifloxacin 400 mg (positive control), and placebo in a crossover design. The maximal placebo‐corrected change in QT interval with pacritinib was −9.7 ms (90% confidence interval: −13.4, −6.1), and all upper confidence bounds were <10 ms. A small, clinically irrelevant inverse concentration–QTc relationship was observed. No subject administered pacritinib had a QTc interval using Fridericia's formula (QTcF) >480 ms or a change from baseline in QTcF >30 ms. Moreover, in the PAC203 trial, there was no correlation between pacritinib exposure and QTcF at weeks 12 or 24. Median QTcF changes from pre‐dose to 4 h post‐dose were minimal (+2.7 and −0.3 ms, respectively), and no dose–response relationship was identified. These findings suggest that pacritinib exposure is unlikely to be correlated with QT prolongation.