Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): Results from two phase I studies in healthy volunteers

• Published in: Clinical pharmacology in drug development Vol. 4; no. 4; pp. 315 - 321
• Main Authors: Zhang, Meng, Xu, Christine, Ma, Lei, Shamiyeh, Elias, Yin, Jianyun, von Moltke, Lisa L., Smith, William B.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.07.2015; Wiley Subscription Services, Inc
• Subjects: Administration, Oral; Adolescent; Adult; Area Under Curve; bioavailability; Biological Availability; Breakfast; Cross-Over Studies; Dietary Fats - administration & dosage; Drug Administration Schedule; Fasting - blood; fedratinib; Food-Drug Interactions; Half-Life; healthy subjects; Healthy Volunteers; Humans; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Janus Kinase Inhibitors - administration & dosage; Janus Kinase Inhibitors - adverse effects; Janus Kinase Inhibitors - blood; Janus Kinase Inhibitors - pharmacokinetics; Male; Metabolic Clearance Rate; Middle Aged; pharmacokinetics; Postprandial Period; Pyrrolidines - administration & dosage; Pyrrolidines - adverse effects; Pyrrolidines - blood; Pyrrolidines - pharmacokinetics; SAR302503; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Tennessee; Young Adult; Tennessee; pharmacokinetics; SAR302503; bioavailability; healthy subjects; fedratinib
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.161

Fedratinib (SAR302503/TG101348) is a Janus kinase 2 (JAK2)‐selective inhibitor developed for treatment of patients with myelofibrosis. The effect of food intake on the pharmacokinetics (PKs) and tolerability of single‐dose fedratinib was investigated in two Phase I studies (FED12258: 100 mg or 500 mg under fasted or fed [high‐fat breakfast] conditions; ALI13451: 500 mg under fasted or fed [low‐ or high‐fat breakfast] conditions) in healthy male subjects. At the 500 mg dose the fed:fasted ratio estimate for area under the plasma concentration—time curve extrapolated to infinity was 0.96 (100 mg; high‐fat/fasted), 1.19–1.24 (500 mg; high‐fat/fasted), and 1.22 (500 mg; low‐fat/fasted). Fedratinib 500 mg attained peak plasma concentration 4 hours after a high‐fat breakfast and 2–2.5 hours after a low‐fat breakfast or under fasted conditions; terminal half‐life was 76–88 hours (fasted) and 73–78 hours (fed). The most frequent adverse events were mild gastrointestinal toxicities, the incidence of which decreased following a high‐fat breakfast compared with both fasted and low‐fat breakfast conditions (17%, 67%, and 59% of subjects, respectively, in ALI13451). In conclusion, food intake had minimal impact on the PKs of fedratinib, and the tolerability of this drug was improved when taken following a high‐fat breakfast.