title: Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): Results from two phase I studies in healthy volunteers.
abstract: 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.
authors.affiliation: Sanofi Clinical and Exploratory Pharmacology, Bridgewater, NJ, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Sanofi Disposition, Safety and Animal Research, Bridgewater, NJ, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Xu
authors.affiliation: Sanofi Disposition, Safety and Animal Research, Bridgewater, NJ, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Sanofi Clinical and Exploratory Pharmacology, Bridgewater, NJ, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Shamiyeh
authors.affiliation: Sanofi Clinical and Exploratory Pharmacology, Bridgewater, NJ, USA.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Sanofi Clinical and Exploratory Pharmacology, Cambridge, MA, USA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: von Moltke
authors.affiliation: Volunteer Research Group, University of Tennessee Medical Center, Knoxville, TN, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D062408:Breakfast; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005215:Fasting / Q000097:blood; D018565:Food-Drug Interactions; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075242:Janus Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D019518:Postprandial Period; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013714:Tennessee; D055815:Young Adult; D000096926:Benzenesulfonamides
chemical_list: D004041:Dietary Fats; D053614:Janus Kinase 2; D000075242:Janus Kinase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human
keywords: SAR302503; bioavailability; fedratinib; healthy subjects; pharmacokinetics