Presentation: RDEA594, a Potential Uric Acid Lowering Agent through Inhibition of Uric Acid Reuptake, Shows Better Pharmacokinetics than its Prodrug RDEA806 (2008)

28 RDEA594, a Potential Uric Acid Lowering Agent through Inhibition of Uric Acid Reuptake, Shows Better Pharmacokinetics than its Prodrug RDEA806

Background: Significant reduction of serum uric acid was discovered in a multiple dose clinical study of RDEA806. The mode of action of has been determined to be associated with the inhibitory effect of RDEA594, a major metabolite of RDEA806, on uric acid re-absorption through the URAT1 renal transporter. In vitro and in vivo experiments have been conducted to evaluate the feasibility and dose range of administering RDEA594 in the clinical setting.
Method: RDEA594 was evaluated in vitro for metabolism profiling as well as P450 reaction phenotyping and drug-drug interaction potential. Exposure and urinary excretion of RDEA594 following RDEA594 dosing was compared to those obtained from RDEA806 dosing in the Sprague-Dawley rat and cynomolgus monkey following single dose. Safety evaluations were conducted following 14-day repeat dosing in monkeys and rats.
Results: RDEA594 was relatively stable following liver microsomal and hepatocytes incubation across species. Both oxidation and glucuronidation metabolites were observed from in vitro metabolism studies in trace amount. Drug-drug interaction potential of RDEA594 was predicted to be low as IC50 were all above 10 uM for five major P450 isoforms tested using HLM. RDEA594 was not mediated by any of the P450 isozyme tested. Following single dosing of RDEA594, exposure of RDEA594 was significantly higher than those obtained from RDEA806 dosing, > 5X at 20 mg/kg in rats and > 10X at 30 mg/kg in monkeys. The fold changes increased at higher dosing. In rat urine, significantly higher amount of RDEA594 (~6%) was excreted into urine following RDEA594 dosing compared to 0.7% following RDEA806 dosing. With no adverse effects noted in clinical conditions and macroscopic evaluation, RDEA594 was well tolerated in both rats and monkeys up to 100 mg/kg.
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Conclusions: RDEA806, a prodrug of RDEA594, exhibited outstanding ability to reduce serum uric acid level at 300 and 500 mg BID (immediate release capsules) and 400 mg BID (modified release capsules) dosing regimens with 400 mg BID showing greatest uric acid reduction (47.9%). Pre-clinical studies show that RDEA594 was stable under in vitro evaluation and exhibited higher exposure following oral dosing in rats and monkeys than from dosing its prodrug RDEA806. In addition, approximately 10X of RDEA594 was recovered in urine following RDEA594 dosing in rat compared to RDEA806 dosing. These findings strongly suggest that a low dosage of RDEA594, as low as 80 mg/day, can be anticipated in future clinical trials to produce similar uric acid reduction results. This dose level is significantly lower than the safety level established in the pre-clinical toxicology program.

  L. Yeh, Ardea Biosciences, 3; J. Yang, Ardea Biosciences, 3; J. Theiss, None; D. Zhou, Ardea Biosciences, 3; R. Yan, Ardea Biosciences, 3; V. Borges, Ardea Biosciences, 3; M. Nguyen, Ardea Biosciences, 3; K. Tieu, Ardea Biosciences, 3; K. Manhard, Ardea Biosciences, 3; B. Quart, Ardea Biosciences, 3.