title: Effects of ketoconazole on the pharmacokinetic properties of CG100649, a novel NSAID: a randomized, open-label crossover study in healthy Korean male volunteers.
abstract: BACKGROUND
  CG100649, a novel selective cyclooxygenase-2 inhibitor that also inhibits carbonic anhydrase I/II, is expected to reduce the cardiovascular risk typical of other NSAIDs. Concurrent medications may influence the activities of the cytochrome P450 (CYP) 3A enzyme through which CG100649 is metabolized.
  
  
  OBJECTIVE
  This study was designed to evaluate the influence of ketoconazole, a known strong inhibitor of CYP3A, on the pharmacokinetic properties of CG100649.
  
  
  METHODS
  This randomized, open-label, 2 × 2 crossover study was conducted in healthy Korean male volunteers. Each subject received the following 2 treatments in a randomly allocated sequence, separated by a washout period of 42 days: single oral dose of CG100649 6 mg, and concurrent dosing of CG100649 6 mg and ketoconazole 400 mg followed by ketoconazole 400 mg/d over 4 days. Blood samples for pharmacokinetic analysis were collected at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 240, 384, and 480 hours after dosing of CG100649 in each sequence. Tolerability assessments were performed throughout the study.
  
  
  RESULTS
  Thirty subjects participated, and 26 subjects completed the study. Seventeen adverse events (AEs) were reported in 10 subjects, and all AEs were recovered without any sequelae. No serious AEs were reported. Six subjects receiving the single dose of CG100649 had 9 AEs, and 7 subjects receiving the combination of ketoconazole and CG100649 had 8 AEs. The Cmax of CG100649 with CG100649 only and with concurrent administration of CG100649 + ketoconazole were similar (10.7 and 11.0 ng/mL, respectively). The CG100649 AUClast with concurrent ketoconazole was 1.29-fold greater than that with CG100649 only (2074.0 and 2685.8 ng · h/mL) and demonstrated a statistically significant difference (P < 0.05). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or AEs between treatments.
  
  
  CONCLUSIONS
  Although the AUC of CG100649 increased by 29% with the concurrent medication of ketoconazole, it is considered that concurrent administration of CG100649 with ketoconazole would not change the safety profile of CG100649.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Youn Choi
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seok-Joon
authors.initials: SJ
authors.lastname: Jin
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Jin Ah
authors.initials: JA
authors.lastname: Jung
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Un-Jib
authors.initials: UJ
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Ju
authors.initials: YJ
authors.lastname: Ko
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: mdhslim@gmail.com.
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004334:Drug Administration Schedule; D004357:Drug Synergism; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D007654:Ketoconazole
keywords: CG100649; COX-2 inhibitor; drug interaction; ketoconazole; pharmacokinetic