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

Oral CG100649 was administered in 3 escalating loading and maintenance dose regimens for 5 days in 47 healthy male and female volunteers. Subjects in Cohort A received 2.0 mg (Day 1) followed by 0.3 mg/day (Days 2-5). Subjects in Cohort B received 4.0 mg (Day 1) followed by 0.6 mg/day. Subjects in Cohort C received 8.0 mg (Day 1) followed by 1.2 mg/day. Within each dose cohort, 12 subjects (6 male, 6 female) were randomized to receive active compound and 4 subjects (2 male, 2 female) received placebo. PK and safety evaluations continued through Day 31. All doses were well tolerated. CG100649 was well absorbed with linear dose-proportionality in among the 3 treatment groups. Inter-subject variability was low (generally 20% or less). Nearly all subjects achieved peak blood & plasma levels in 4-8 hours after the initial loading dose and maintained approximately steady-state blood levels for the remaining 4 days. Due to its preferential high-affinity binding to red blood cell carbonic anhydrase (CA), CG100649 showed 85-100x higher concentrations in whole blood than plasma in all 3 dose cohorts, in both males and females, from Day 1 through Day 5. The terminal half-life in both blood and plasma was 5-6 days. One female subject in Cohort C appeared to have faster drug elimination; progressively declining blood levels were observed from Days 2-5; plasma levels were maintained at steady-state. No gender differences were apparent in drug exposure. Consistent with its potent CA inhibitory activity, dose-related increases were observed in serum chloride (females more than males) and in plasma aldosterone (females possibly more than males). These data provide the first evidence of a COX-2 inhibitor with functional CA activity which may improve its overall safety profile by reducing effective free concentrations in tissues with high CA activity. Supported by a grant from CrystalGenomics.