CG100649, a Novel Dual-Acting COX-2 and Carbonic Anhydrase Inhibitor: Ascending Single Dose and Multi-Dose Pharmacokinetics and Safety Evaluation in Healthy Male Subjects

CG100649 is a novel dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA) inhibitor which is being developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. Single oral doses of 1 mg, 5 mg, 8 mg, and 12 mg of CG100649 were well tolerated when given to healthy male subjects (N=4 active and 2 placebo subjects per dose). There was statistically significant evidence for a linear dose-proportional increase, on average, in systemic exposure to CG100649 as measured by C_max. Single-dose CG100649 demonstrates a long terminal elimination half-life of approximately 5 days. Multiple doses consisting of a single loading dose followed by daily maintenance doses over 7 days (Group 1: 3 mg/0.4 mg/day; Group 2: 6 mg/0.8 mg/day; N=6 active and 2 placebo subjects per dose) demonstrated rapid achievement of steady state and consistent systemic exposure. After repeated daily dosing, the degree of accumulation of CG100649 in plasma (Ro) on Day 8 was not appreciably different from that observed on Day 1. On average, Ro values ranged from 1.1 to 1.2, consistent with rapid achievement of steady-state following a loading dose. Plasma CG100649 concentrations of 4 to 5 ng/mL (Group 1) and 6 to 9 ng/mL (Group 2) were maintained during the repeat-dose regimen. Maximum plasma concentrations of CG100649 were reached at approximately 3 to 12 h post dose; thereafter, plasma CG100649 concentrations declined with a mean apparent terminal half life of approximately 100 to 109 h. Extrapolating from the preclinical efficacy data, the plasma concentrations with the higher maintenance dose regimen exceeded probable therapeutic concentrations by at least four fold. All doses were well tolerated. Use of a loading dose + reduced maintenance dose regimen may reduce the time to reach steady state plasma concentrations to approximately one day. Supported by a grant from CrystalGenomics.