Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies

British Journal of Clinical Pharmacology

Volumn 76, Issue 1, 2013, Pages 78-88

  Baluom, Muhammad ^a   Grossbard, Elliott B ^a   Mant, Tim ^b   Lau, David T W ^a  

^a RIGEL PHARMACEUTICALS INC   (United States)

^b GUY S HOSPITAL   (United Kingdom)

Author keywords

First in man studies; Food effect; Fostamatinib; Pharmacokinetics; Rheumatoid arthritis; SYK inhibitor

Indexed keywords

FOSTAMATINIB; PLACEBO;

ABDOMINAL PAIN; ADULT; ARTICLE; CONTROLLED STUDY; CROSSOVER PROCEDURE; DIET RESTRICTION; DOUBLE BLIND PROCEDURE; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG DOSAGE FORM COMPARISON; DRUG HALF LIFE; FEMALE; FOOD DRUG INTERACTION; HUMAN; HUMAN EXPERIMENT; MALE; NAUSEA; NORMAL HUMAN; POSITIONAL DIZZINESS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHEUMATOID ARTHRITIS; SORE THROAT; STEADY STATE; SUSPENSION; TABLET; VOMITING;

ADMINISTRATION, ORAL; ADOLESCENT; ADULT; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; DRUG ADMINISTRATION SCHEDULE; FEMALE; FOOD-DRUG INTERACTIONS; HALF-LIFE; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MALE; MIDDLE AGED; OXAZINES; PHARMACEUTICAL SOLUTIONS; PRODRUGS; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; PYRIDINES; SUSPENSIONS; TABLETS; YOUNG ADULT;

EID: 84879083820     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.12048     Document Type: Article

References (24)

1. Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL. Tyrosine kinase SYK: essential functions for immunoreceptor signaling. Immunol Today 2000; 21: 148-54.
2. Berton G, Mocsai A, Lowell CA. Src and Syk kinases: key regulators of phagocytic cell activation. Trends Immunol 2005; 26: 208-14.
3. Nimmerjahn F, Ravetch JV. Fcg receptors: old friends and new family members. Immunity 2006; 24: 19-28.
4. Singh R,Masuda ES. Spleen tyrosine kinase (SYK) biology, inhibitors and therapeutic applications. Annu Rep Med Chem 2007; 42: 379-91.
5. Wong BR, Grossbard EB, Payan DG,Masuda ES. Targeting Syk as a treatment for allergic and autoimmune disorders. Expert Opin Investig Drugs 2004; 13: 743-62.
6. Braselmann S, Taylor V, Zhao H,Wang S, Sylvain C, Baluom M, Qu K, Herlaar E, Lau A, Young C,Wong BR, Lovell S, Sun T, Park G, Argade A, Jurcevic S, Pine P, Singh R, Grossbard EB, Payan DG,Masuda ES. R406, an orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006; 319: 998-1008.
7. Pine PR, Chang B, Schoettler N, Banquerigo ML,Wang S, Lau A, Zhao F, Grossbard EB, Payan DG, Brahn E. Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. Clin Immunol 2007; 124: 244-57.
8. Food and Drug Administration, ed. Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. Rockville, MD: US Department of Health and Human Services. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2002.
9. Baluom M, Samara E, Grossbard EB, Lau D. Fostamatinib, a Syk-kinase inhibitor, does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients. J Clin Pharmacol 2011; 51: 1310-8.
10. Weinblatt ME, Kavanaugh A, Burgos-Vargas R, Dikranian AH, Medrano-Ramirez G, Morales-Torres JL, Murphy FT, Musser TK, Straniero N, Vicente-Gonzales AV, Grossbard E. Treatment of rheumatoid arthritis with a SYK kinase inhibitor: a twelve week, randomized, placebo-controlled trial. Arthritis Rheum 2008; 58: 3309-18.
11. Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB,Magilavy DB. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med 2010; 363: 1303-12.
12. Genovese MC, Kavanaugh A,Weinblatt ME, Peterfy C, DiCarlo J, White ML, O'Brien M, Grossbard EB,Magilavy DB. An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents. Arthritis Rheum 2011; 63: 337-45.
13. Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel JB. Of mice and men: an open-label pilot study for the treatment of immune thrombocytopenic purpura by and inhibitor of Syk. Blood 2009; 113: 3133-4.
14. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, Shipp MA. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115: 2578-85.
15. Chang T, Benet L, Hebert MF. The effect of water-soluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1996; 59: 297-303.
16. Stella VJ, Nti-Addae KW. Prodrug strategies to overcome poor water solubility. Adv Drug Deliv Rev 2007; 59: 677-94.
17. Stella VJ. Prodrugs: some thoughts and current issues. J Pharm Sci 2010; 99: 4755-65.
18. Stella VJ. Case study: fosphenytoin: a prodrug of phenytoin. Biotechnology 2007; V: (Pt 5): 1259-67.
19. Panini SR, Lehrer G, Rogers DH, Rudney H. Distribution of 3-hydroxy-3-methylglutaryl coenzyme A reductase and alkaline phosphatase activities in isolated ileal epithelial cells of fed, fasted, cholestyramine-fed, and 4-aminopyrazolo[3,4-d]pyrimidine-treated rats. J Lipid Res 1979; 20: 879-89.
20. Heimbach T, Oh DM, Li LY, Rodríguez-Hornedo N, Garcia G, Fleisher D. Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs. Int J Pharm 2003; 261: 81-92.
21. Sweeny DJ, Li W, Grossbard E, Lau DT. Contribution of gut bacteria to the metabolism of the spleen tyrosine kinase (Syk) inhibitor R406 in cynomolgus monkey. Xenobiotica 2010; 40: 415-23.
22. Sweeny DJ, Li W, Clough J, Sweeny DJ, Li W, Clough J, Bhamidipati S, Singh R, Park G, Baluom M, Grossbard E, Lau DT.Metabolism of fostamatinib, the oral methylene phosphate prodrug of the spleen tyrosine kinase inhibitor R406, in humans: contribution of hepatic and gut bacterial processes to the overall biotransformation. Drug Metab Dispos 2010; 38: 1166-76.
23. Small DS, Farid NA, Payne CD, Konkoy CS, Jakubowski JA, Winters KJ, Salazar DE. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of prasugrel. Clin Pharmacokinet 2010; 49: 777-98.
24. Custodio JM,Wu CY, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev 2008; 60: 717-33.