Background BCX4208 is an oral, once-daily, purine nucleoside phosphorylase (PNP) inhibitor in clinical development as add-on therapy for the chronic management of hyperuricemia in patients with gout. Based on the role of PNP in purine catabolism, inhibiting PNP should reduce hypoxanthine (HX), xanthine (X) and uric acid levels. The combination of BCX4208 with allopurinol produces a synergistic reduction in serum uric acid (sUA) in gout patients1. Plasma X and HX concentrations are significantly higher in untreated gout patients compared to hyperuricemic and normal subjects2. Elevated plasma X and HX concentrations are also associated with kidney stones, as seen in XO deficient patients and mice3,4.
Objectives To measure plasma X and HX concentrations in gout patients receiving 300 mg/d allopurinol plus either placebo or BCX4208.
Methods 278 subjects with gout and sUA ≥6.0 mg/dL on allopurinol 300 mg/d for at least 2 weeks were randomized to receive oral BCX4208 at 5, 10, 20, or 40 mg/d or placebo for 12 weeks while continuing allopurinol 300 mg/d. Blood samples were collected at baseline and day 85 into heparin tubes containing BCX-34 (PNP inhibitor) to prevent purine metabolism during collection and processing. Plasma concentrations of X and HX were analyzed by LC/MS/MS. Due to the high levels of endogenous X and HX present in the control matrix, [15N2] xanthine and [D2] hypoxanthine were used to generate the standard curve for quantification of plasma X and HX concentrations. Using this method, in normal healthy subjects the mean (± SD) concentrations of plasma X and HX were 56 (± 13) ng/ml and <25 ng/ml respectively.
Results BCX4208 combined with allopurinol produced significant reductions in plasma X and HX concentrations from baseline, compared to placebo (Table). At baseline (subjects on allopurinol 300 mg/d) the mean (± SD) concentrations of the plasma X and HX were 500 (± 408) ng/ml and 301 (± 293) ng/ml, respectively. The reduction in mean plasma X and HX concentrations with BCX4208 treatment in gout subjects was dose-dependent.
Conclusions Using a robust LC/MS/MS method and stabilization of plasma X and HX during processing, oral BCX4208 administration demonstrated dose-dependent mean reductions in plasma X and HX concentrations in gout patients while under treatment with allopurinol. These results confirm the mechanism of action of BCX4208.
 Hollister AS, et al. Ann Rheum Dis 2011; 70 (Suppl 3): 183
 Zhao J, et al. Clinical Chemistry 51, No. 9, 2005
 Gragan T, et al. Saudi. J. Kidney Dis Transpl 2010; 21 (2):328
 Ohtsubo T, et al. Hypertension 2009; 54:868-876.
Disclosure of Interest S. Bantia Employee of: BioCryst Pharmaceuticals, C. Parker Employee of: BioCryst Pharmaceuticals, L. Harman Employee of: BioCryst Pharmaceuticals, D. Papac Consultant for: BioCryst Pharmaceuticals, A. Hollister Employee of: BioCryst Pharmaceuticals
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