Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies

• Published in: European journal of clinical pharmacology 2016-01, Vol.72 (1), p.61-71
• Main Authors: Martin, Paul, Cheung, S. Y. Amy, Yen, Mark, Han, David, Gillen, Michael
• Format: Article
• Language: English
• Subjects: Adult; Asian Continental Ancestry Group; Biomedical and Life Sciences; Biomedicine; Blood; Double-Blind Method; Erythrocytes - metabolism; Female; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Kinetics; Male; Oxazines - blood; Oxazines - pharmacokinetics; Oxazines - urine; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyridines - blood; Pyridines - pharmacokinetics; Pyridines - urine; Rheumatoid arthritis; Studies; Syk Kinase; Young Adult
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-015-1961-5

Purpose The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. Methods In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. Results Mean maximum plasma concentration ( C max ) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (