Background/Purpose:

URC102, a novel and potent inhibitor of human uric acid transporter 1 (hURAT1), is currently under clinical development to treat patients with gout. In preclinical studies, URC102 inhibited URAT1 more selectively leading to more potent uricosuric and hypouricemic effects than conventional uricosuric agents such as benzbromarone. A phase I study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability profiles of URC102 after single and multiple oral administrations.

Methods:

A randomized, double-blind, placebo-controlled, single and multiple dose-escalation study was conducted in healthy male volunteers. Thirty-one healthy Koreans randomly received a single oral dose of placebo or URC102 1, 3, 10 or 30 mg and twenty-four Caucasian received 1, 3 and 10 mg in the fasting state. Furthermore, 44 healthy Koreans received repeated doses of placebo or URC102 1, 3, 5, 7 or 10 mg for 7 consecutive days. Blood and urine samples were collected up to 168 hours post-dose in the single ascending dose study, and up to 312 (blood) and 168 (urine) hours post-dose in the multiple dose study. Serum uric acid, urinary uric acid output, and fractional excretion of uric acid were the PD variables. Safety and tolerability were also evaluated based on monitoring of physical conditions, vital signs, electrocardiograms, and clinical laboratory tests.

Results: The maximum plasma concentration (C_max) and the area under the plasma concentration-time curve up to the last measurable time (AUC_last) increased as the dose increased in both single (1 to 30 mg) and multiple ascending dose (1 to 10 mg) studies. URC102 was rapidly absorbed after single and repeated doses (time to reach C_max or T_max less than 2 and 1 to 6 hours, respectively). Blood or urine PK characteristics of URC102 were not significantly different between Koreans and Caucasians. The serum uric acid levels were rapidly reduced after single and repeated administrations of URC102. The maximum mean decrease in serum uric acid from baseline was more than 70% after repeated oral doses of URC102 at 5 to 10 mg. No serious AE was reported, and all AEs were resolved.

Conclusion:

Orally administered URC102 was well tolerated over the dose range of 1 to 10 mg after single and multiple once-daily administrations for 7 days, and showed a linear PK profile in the ranges of 1 to 30 mg (single dose) and 1 to 10 mg (multiple doses). URC102 was effective in lowering serum uric acid levels.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-pharmacokinetic-and-pharmacodynamic-evaluation-of-urc102-a-potent-and-selective-inhibitor-of-urat1-after-single-and-multiple-oral-administrations-in-healthy-volunteers/