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

<jats:sec><jats:title>Aim</jats:title><jats:p>Fostamatinib (<jats:styled-content style="fixed-case">R788</jats:styled-content>) is an orally dosed prodrug designed to deliver the active metabolite <jats:styled-content style="fixed-case">R940406</jats:styled-content> (<jats:styled-content style="fixed-case">R406</jats:styled-content>), a spleen tyrosine kinase (<jats:styled-content style="fixed-case">SYK</jats:styled-content>) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and <jats:styled-content style="fixed-case">R406</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>Three clinical studies were conducted in healthy subjects: (<jats:styled-content style="fixed-case">A</jats:styled-content>) A single ascending dose study for <jats:styled-content style="fixed-case">R406</jats:styled-content> with doses ranging from 80–600 mg, (<jats:styled-content style="fixed-case">B</jats:styled-content>) a single‐ and multiple‐dose study of fostamatinib in aqueous suspension, with single doses ranging from 80–400 mg and multiple doses at 160 mg twice daily and (<jats:styled-content style="fixed-case">C</jats:styled-content>) a study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>These studies demonstrated that when administered as a solution, <jats:styled-content style="fixed-case">R406</jats:styled-content> was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half‐life of 12–21 h was observed. Similar <jats:styled-content style="fixed-case">R406</jats:styled-content> exposure could be achieved with fostamatinib suspension and steady‐state was achieved after 3–4 days following twice daily administration. Fostamatinib tablet and suspension exhibited similar <jats:styled-content style="fixed-case">R406</jats:styled-content> exposure. Upon co‐administration with food, a delay in peak time and lower peak concentrations of <jats:styled-content style="fixed-case">R406</jats:styled-content> were observed but at the same time the overall exposure did not change.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Fostamatinib demonstrates rapid and extensive conversion to <jats:styled-content style="fixed-case">R406</jats:styled-content>, an inhibitor of <jats:styled-content style="fixed-case">SYK</jats:styled-content>. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of <jats:styled-content style="fixed-case">R406</jats:styled-content>. The <jats:styled-content style="fixed-case">PK</jats:styled-content> profile of <jats:styled-content style="fixed-case">R406</jats:styled-content> could potentially allow once daily or twice daily oral administration of fostamatinib.</jats:p></jats:sec>