Background Fostamatinib (R788), a spleen tyrosine kinase inhibitor, is currently being developed as an oral therapy for patients with rheumatoid arthritis¹. In humans, orally administered fostamatinib is converted to the active moiety, R406. Elimination into the urine accounts for 19% of the administered dose (<1% of dose is excreted as R406 in urine) with 80% of the total drug recovered in faeces². We hypothesised that renal impairment would not affect R406 exposure.

Objectives To assess R406 pharmacokinetics in healthy subjects and subjects with renal impairment.

Methods A total of 24 subjects were enrolled in the phase I study (NCT01245790) and stratified into three equal groups based on creatinine clearance rates (CL_CR) as follows: normal renal function (CL_CR ≥80 mL/min), moderate renal impairment (CL_CR ≥30 to <50 mL/min), and end-stage renal disease (ESRD; requiring dialysis). Subjects with normal renal function and ESRD were enrolled first, followed by the group with moderate renal impairment. Subjects with normal and moderate renal function received a single oral dose of 150 mg fostamatinib, while those with ESRD received two oral doses of 150 mg fostamatinib with a 1-week washout period between doses. The first dose was taken post-dialysis and the second dose 2 h pre-dialysis. Blood samples were collected pre-dose and up to 72 h post-dose. Urine was collected pre-dose from –12 to 0 h, and during 6-h intervals up to 48-h post-dose to determine the concentrations of R406 and its N-glucuronide metabolite.

Results R406 C_max and AUC geometric means were lower in the renally impaired groups when compared to the normal renal function group while the median t_maxwas similar across all treatment groups. In ESRD subjects, R406 exposure was lower post-dialysis compared with pre-dialysis. Urinary excretion of R406 N-glucuronide was lower with increasing severity of renal impairment. Renal elimination of R406 was negligible (less than 0.1% of administered dose) in all treatment groups. There were no statistically significant relationships between R406 exposure and CL_CR. Eleven subjects reported ≥1 adverse event with nausea being the most common. There were no deaths or serious adverse events reported.

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Conclusions Renal impairment did not affect the exposure of the active metabolite R406 to an extent that would be considered clinically relevant. Consequently, there is no expectation of a need for fostamatinib dose reduction in renally impaired subjects.

1. Baluom M, et al. Clin Pharmacol 2011;51:1310–1318.

2. Sweeny DJ, et al. Drug Metab Dispos 2010;38:1166–1176.

Disclosure of Interest P. Martin Shareholder of: AstraZeneca Pharmaceuticals, Employee of: AstraZeneca Pharmaceuticals, S. Oliver Shareholder of: AstraZeneca Pharmaceuticals, Employee of: AstraZeneca Pharmaceuticals, M. Gillen Shareholder of: AstraZeneca Pharmaceuticals, Employee of: AstraZeneca Pharmaceuticals, T. Marbury: None Declared, D. Millson Shareholder of: AstraZeneca Pharmaceuticals, Employee of: AstraZeneca Pharmaceuticals