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.
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 ± 33 hours, respectively, after administration of oral single doses of 2 or 8 mg 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/70 kg, and for volume of distribution, 559 (6.7) and 7.6 (2.4) L/70 kg, 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.
Clinical Pharmacology & Therapeutics Division, Kinetic Modeling and Simulation (KMAS) Core, The Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA.|Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia, PA, USA.
Sarapee
S
Hirankarn
Clinical Pharmacology & Therapeutics Division, Kinetic Modeling and Simulation (KMAS) Core, The Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA.|Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia, PA, USA.
Jeffrey S
JS
Barrett
Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia, PA, USA.|Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Naji
N
Alamuddin
Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia, PA, USA.|Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Garret A
GA
FitzGerald
Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia, PA, USA.|Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Carsten
C
Skarke
CG100649; carbonic anhydrase; cyclooxygenase; human; inhibition; pharmacokinetics