AB0887 Pharmacokinetics, pharmacodynamics, and tolerability of verinurad (RDEA3170), a selective uric acid reabsorption inhibitor, in healthy japanese male subjects

Abstract

Background: 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. Objectives: The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy Japanese and non- Asian adult male subjects. Methods: 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). Results: 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 [Cmax] and area under the plasma concentration-time curve [AUC]) increased in a near dose-proportional manner under fasted or fed conditions. The time to Cmax (Tmax) was approximately 1.25-2.0 hours post-dose under fasted conditions. A moderate-fat meal delayed Tmax 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. Cmax 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. Conclusions: 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.