Drug Design, Development and Therapy (Jun 2018)
Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy Japanese and non-Asian male subjects
Abstract
Jesse Hall,1 Michael Gillen,2 Sha Liu,1 Jeffrey N Miner,1 Shakti Valdez,1 Zancong Shen,1 Caroline Lee1 1Ardea Biosciences, Inc., San Diego, CA, USA; 2AstraZeneca, Gaithersburg, MD, USA Purpose: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of gout and asymptomatic hyperuricemia. This study evaluated verinurad pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and non-Asian adult male subjects.Methods: This was a Phase I, randomized, single-blind, placebo-controlled study. Panels of 8 Japanese subjects were randomized to receive oral verinurad (2.5–15 mg) or placebo administered as a single dose in a fasted and fed state and as once-daily doses for 7 days in a fed state. Eight non-Asian subjects received verinurad 10 mg as a single dose (fasted and fed) and multiple doses in the fed state. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events and laboratory data.Results: Of 48 randomized subjects, 46 (Japanese, 39; non-Asian, 7) completed the study. Following single or multiple doses in Japanese subjects, maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a near dose-proportional manner. Time to Cmax (Tmax) was ~1.25–2.0 hours with fasting. A moderate-fat meal delayed Tmax (range 3.0–5.0 hours) and had a variable effect on AUC (0%–97% increase) and Cmax (0%–26% increase) across the dose groups. Following multiple verinurad 10 mg doses, Cmax and AUC were 38% and 23% higher, respectively, in Japanese vs non-Asian subjects, largely due to body weight differences. Mean reduction of serum urate following multiple verinurad 10 mg doses was 46% and 44% after 24 hours in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses.Conclusion: Verinurad monotherapy lowered serum urate and was well tolerated in both healthy Japanese and non-Asian males, while small differences in plasma pharmacokinetics were observed. These data support further evaluation of once-daily verinurad as a treatment for gout and asymptomatic hyperuricemia. Keywords: pharmacokinetics, pharmacodynamics, selective uric acid reabsorption inhibitor, serum urate, urinary uric acid
