AB0887 Pharmacokinetics, pharmacodynamics, and tolerability of verinurad (RDEA3170), a selective uric acid reabsorption inhibitor, in healthy japanese male subjects
Authors: M Gillen, JN Miner, S Valdez
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Chronic gout is a significant clinical problem in Asia, including Japan, where many patients remain suboptimally treated with currently available therapies. Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. <h3>Objectives</h3> The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy Japanese and non-Asian adult male subjects. <h3>Methods</h3> This was a Phase 1, randomized, single-blind, placebo-controlled study (NCT01872832). Panels of 8 Japanese male subjects were randomized in a 3:1 ratio to receive a modified-release formulation of oral verinurad (2.5 mg, 5 mg, 10 mg, 15 mg) or placebo administered as a single dose in a fasted state and as multiple once-daily doses in a fed state for 7 days. A panel of 8 non-Asian male subjects received single and multiple doses of oral verinurad (10 mg) or placebo. Serial plasma/serum and urine samples were assayed for verinurad and uric acid at predetermined time points. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). <h3>Results</h3> Of 48 randomized subjects, 46 (Japanese: 39, non-Asian: 7) completed the study. Treatment groups were generally well balanced; however, mean body weight and body mass index were approximately 14% and 7% lower, respectively, in Japanese than non-Asian subjects. Following single- or multiple-oral doses of verinurad in Japanese subjects, exposure (maximum plasma concentration [C<sub>max</sub>] and area under the plasma concentration-time curve [AUC]) increased in a near dose-proportional manner under fasted or fed conditions. The time to C<sub>max</sub> (T<sub>max</sub>) was approximately 1.25–2.0 hours post-dose under fasted conditions. A moderate-fat meal delayed T<sub>max</sub> up to 5 hours post-dose and increased plasma verinurad exposures up to 109%. Following once-daily multiple doses, there was modest accumulation of verinurad. C<sub>max</sub> and AUC were 38% and 23% higher, respectively, in Japanese versus non-Asian subjects, largely due to the difference in body weight. Mean reductions in serum uric acid following once-daily multiple dosing of verinurad 10 mg were 62% and 58% at maximum reduction and 46% and 44% at 24 hours post-dose in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses. One Japanese subject discontinued verinurad due to an AE of urticaria that resolved after 11 days. No serious AEs, Grade 3 or 4 AEs, or clinically significant laboratory or ECG abnormalities were noted. <h3>Conclusions</h3> Verinurad significantly lowered serum uric acid and was well tolerated in both healthy Japanese and non-Asian males, despite small differences in plasma pharmacokinetics. These data support further evaluation of once-daily verinurad as a treatment for hyperuricemia with or without gout in the Japanese population. <h3>Acknowledgements</h3> The authors thank Caroline Lee and Zancong Shen of Ardea Biosciences, Inc., for critical review of the abstract. <h3>Disclosure of Interest</h3> M. Gillen Employee of: AstraZeneca, J. Miner Employee of: Ardea Biosciences, Inc., S. Valdez Employee of: Ardea Biosciences, Inc.