Fostamatinib, a Syk-Kinase Inhibitor, Does Not Affect Methotrexate Pharmacokinetics in Patients With Rheumatoid Arthritis

• Published in: Journal of clinical pharmacology Vol. 51; no. 9; pp. 1310 - 1318
• Main Authors: Baluom, Muhammad, Samara, Emil, Grossbard, Elliott B., Lau, David T.-W.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2011; Wiley Subscription Services, Inc
• Subjects: 7-hydroxymethotrexate; Antirheumatic Agents - pharmacokinetics; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - enzymology; Arthritis, Rheumatoid - metabolism; Confidence intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions - physiology; Female; Fostamatinib; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Male; Methotrexate; Methotrexate - pharmacokinetics; Methotrexate - therapeutic use; Middle Aged; Oxazines - pharmacokinetics; Oxazines - therapeutic use; pharmacokinetics; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyridines - pharmacokinetics; Pyridines - therapeutic use; Rheumatism; Rheumatoid arthritis; Syk Kinase
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270010381496

Fostamatinib (R788) is being investigated as an add‐on therapy for the treatment of rheumatoid arthritis (RA) in patients with inadequate response to methotrexate (MTX). This study evaluated the potential pharmacokinetic interaction between R788 and MTX. Sixteen RA subjects on a stable weekly MTX regimen were enrolled and received MTX on days 1 and 8. Twelve subjects received 100 mg of R788 orally, and 4 subjects received a matching placebo twice daily from days 4 to 8 and once daily on days 3 and 9. Blood samples were collected on days 1 and 8 for MTX and 7‐hydroxymethotrexate (7‐OH‐MTX), and days 3 and 9 for R788 and its active metabolite, R406. MTX and 7‐OH‐MTX pharmacokinetic parameters were similar on days 1 and 8. In the R788 group, the mean day 8 to day 1 ratios (90% confidence intervals) of maximum concentration and area under the plasma concentration—time curve estimates were 1.01 (0.85–1.20) and 1.12 (0.90–1.40) for MTX and 1.06 (0.82–1.35) and 1.06 (0.83–1.36) for 7‐OH‐MTX, respectively. Urinary excretion of MTX and 7‐OH‐MTX was also similar with or without R788, averaging 58% to 69% and 4% to 5% of the MTX dose, respectively. The data suggest that there is no clinically significant pharmacokinetic interaction of R788 and MTX in RA patients.