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

• Published in: Cancer chemotherapy and pharmacology Vol. 85; no. 6; pp. 1109 - 1117
• Main Authors: Ogasawara, Ken, Smith, William B., Xu, Christine, Yin, Jian, Palmisano, Maria, Krishna, Gopal
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2020; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Area Under Curve; Cancer Research; Case-Control Studies; Dosage; End-stage renal disease; Enzyme inhibitors; Female; Follow-Up Studies; Humans; Janus kinase; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Kidney diseases; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - enzymology; Kidney Failure, Chronic - pathology; Liver diseases; Liver Diseases - drug therapy; Liver Diseases - enzymology; Liver Diseases - pathology; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Myelofibrosis; Oncology; Original Article; Pharmacokinetics; Pharmacology/Toxicology; Prognosis; Pyrrolidines - administration & dosage; Pyrrolidines - pharmacokinetics; Studies; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Survival Rate; Tissue Distribution; Young Adult; Tolerability; Hepatic impairment; Renal impairment; Fedratinib; Pharmacokinetics
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-020-04084-2

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.