Pharmacokinetics and tolerability of fedratinib, an oral, selective Janus kinase 2 inhibitor, in subjects with renal or hepatic impairment
- 1 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Chemotherapy and Pharmacology
- Vol. 85 (6), 1109-1117
- https://doi.org/10.1007/s00280-020-04084-2
Abstract
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.Funding Information
- Bristol-Myers Squibb
This publication has 22 references indexed in Scilit:
- A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosisBlood Cancer Journal, 2015
- Effect of food on the bioavailability and tolerability of the JAK2‐selective inhibitor fedratinib (SAR302503): Results from two phase I studies in healthy volunteersClinical Pharmacology in Drug Development, 2014
- A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteersThe Journal of Clinical Pharmacology, 2013
- Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in MyelofibrosisJournal of Clinical Oncology, 2011
- Pharmacokinetics and dosage adjustment in patients with renal dysfunctionEuropean Journal of Clinical Pharmacology, 2009
- New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and TreatmentBlood, 2009
- Portal hypertension secondary to myelofibrosis with myeloid metaplasia: A study of 13 casesWorld Journal of Gastroenterology, 2009
- Pharmacokinetics and dosage adjustment in patients with hepatic dysfunctionEuropean Journal of Clinical Pharmacology, 2008
- Effect of hepatic insufficiency on pharmacokinetics and drug dosing.International Journal of Clinical Pharmacy, 1998
- Pharmacokinetic effects of altered plasma protein binding of drugs in renal diseaseEuropean Journal of Drug Metabolism and Pharmacokinetics, 1984