Pharmacokinetics and tolerability of fedratinib, an oral, selective Janus kinase 2 inhibitor, in subjects with renal or hepatic impairment.

Purpose: Fedratinib is an oral, selective Janus kinase 2 inhibitor that is approved in the United States for the treatment of patients with intermediate-2 or high-risk myelofibrosis. Pharmacokinetics and tolerability of fedratinib in subjects with renal impairment (RI) and hepatic impairment (HI) were evaluated in two separate studies.
Methods: In the renal study, male and female subjects with stable, chronic mild, moderate, and severe RI, as well as those with end-stage renal disease, were included. The hepatic study included subjects with stable, chronic mild HI. Both were phase 1, multicenter, open-label, single-dose studies, and included matched healthy subjects. Subjects received a single oral dose of fedratinib 300 mg on day 1, were discharged on day 4, returned for clinical visits on days 5-12, and had their end-of-study visit between days 14 and 16.
Results: Thirty-six and 17 subjects were included in the renal and hepatic studies, respectively. In the renal study, fedratinib area under the plasma concentration-time curve from time 0 to infinity (AUC _inf ) was 1.9- and 1.5-fold higher in subjects with severe and moderate RI, respectively, than in matched healthy subjects. In the hepatic study, fedratinib AUC _inf did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment-emergent adverse events were gastrointestinal and mild.
Conclusion: Mild RI and HI do not necessitate fedratinib dosage adjustments. Subjects with moderate RI should be monitored (with dosage adjustments made as necessary), whereas those with severe RI should receive a daily dose of 200 mg, reduced from the indicated dose of 400 mg.