GCG100649, a novel cyclooxygenase-2 inhibitor, exhibits a drug disposition profile in healthy volunteers compatible with high affinity to carbonic anhydrase-i/ii: Preliminary dose-exposure relationships to define clinical development strategies

摘要

CG100649, proposed as a dual inhibitor of cyclooxygenase (COX)-2 and carbonic anhydrase (CA)-I/-II, is long-lived in plasma and whole blood. The mean±SD half-lives were 131±19 and 127±33hours, respectively, after administration of oral single doses of 2 or 8mg CG100649 to healthy volunteers. The whole blood to plasma concentration ratio (78±23) for CG100649 is linear over the dosing interval reflecting a biodistribution pattern consistent with other strong CA-inhibitors (e.g., acetazolamide, methazolamide). A one compartment model with first order absorption and elimination described CG100649 concentration-time profiles well. Estimates (%relative SD) between plasma and whole blood were in agreement for the absorption rate constant, 1.54 (58.6) and 1.43 (28.0)hour-1, respectively, but considerably different for clearance, 3.29 (10.4) and 0.04 (7.7)L/h/70kg, and for volume of distribution, 559 (6.7) and 7.6 (2.4)L/70kg, respectively. The extent to which these unique PK characteristics of CG100649 discriminate it from other COX-2 inhibitors will be the subject of future investigation.