title: Pharmacokinetic, pharmacodynamic, and safety/tolerability profiles of CG100649, a novel COX-2 inhibitor: results of a phase i, randomized, multiple-dose study in healthy Korean men and women.
abstract: BACKGROUND
  CG100649 is a novel anti-inflammatory drug that is currently under development. CG100649 demonstrates a dual mechanism of action on cyclooxygenase-2 and carbonic anhydrase that may result in favorable treatment effects and few adverse gastrointestinal and cardiovascular events.
  
  
  OBJECTIVE
  The objective of this study was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of administering multiple oral doses of CG100649 to healthy Korean volunteers.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled, multiple ascending oral dose study that was performed on 8 male and 8 female subjects per dose cohort. Each subject was randomly selected to receive either a single loading dose followed by 6 days of once-daily placebo (n = 4; 2 male and 2 female subjects) or CG100649 (n = 12; 6 male and 6 female subjects). Each subject was administered 1 of 3 sequential dose levels (8-mg loading dose + 2 mg/d, 10-mg loading dose + 4 mg/d, or 12-mg loading dose + 8 mg/d). Blood samples for pharmacokinetic analysis were obtained ≤480 hours after the last dose. Blood samples for measuring serum thromboxane B2 (TXB2) and ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2) (markers of cyclooxygenase-1 and cyclooxygenase-2 activity, respectively) and urine samples for measuring prostanoid metabolites were collected ≤21 days after the last dose.
  
  
  RESULTS
  During steady state, the median Tmax in blood and plasma after the last dose ranged from 3 to 10 hours and 3.5 to 7.3 hours, respectively. Mean terminal t½ values in blood and plasma ranged from 121 to 203 hours and 100 to 167 hours, respectively. Whole blood concentrations were 50 to 70 times higher than plasma concentrations in all 3 dose cohorts in both male and female subjects. Compared with baseline, serum TXB2 diminished by 68% to 91% at 8 hours after the administration of the last dose in all 3 cohorts (P < 0.001). Ex vivo lipopolysaccharide-stimulated PGE2 was maximally inhibited (89%-96%; P < 0.001) by all 3 dose levels on day 7. Urinary prostacyclin metabolite was inhibited by 64% (P < 0.001) on day 7 (12-24 hours) but only by the highest CG100649 dose. There were no clinically significant drug-related changes in blood pressure between treatment groups. The most frequently encountered adverse events were aphthous stomatitis and dyspepsia.
  
  
  CONCLUSIONS
  CG100649 was well tolerated and demonstrated a whole blood concentration that is ~50 to 70 times higher than in plasma in these healthy subjects. CG100649 suppressed TXB2 and PGE2 at all 3 doses, and only the highest dose suppressed the urinary excretion of the urinary prostacyclin metabolite.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, South Korea; University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Mi Jo
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, South Korea; University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Asan Medical Center, Seoul, South Korea.
authors.forename: Seokjoon
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, South Korea.
authors.forename: Jin Ah
authors.initials: JA
authors.lastname: Jung
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, South Korea; University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, South Korea; University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Yo Han
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, South Korea; University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: ksbae@amc.seoul.kr.
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
mesh_terms: D000284:Administration, Oral; D000328:Adult; D044466:Asian People; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D005663:Furans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000599293:CG100649; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; D013449:Sulfonamides
keywords: COX-2 inhibitor; NSIADs; carbonic anhydrase; prostacyclin; thromboxane