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 CG100...

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Bibliographic Details
Published in:Clinical therapeutics 2014, Vol.36 (1), p.115-125
Main Authors: Choi, Hee Youn, MD, Jin, Seok-Joon, MD, PhD, Jung, Jin Ah, MD, PhD, Kim, Un-Jib, MD, Ko, Young-Ju, MD, Noh, Yook-Hwan, MD, Bae, Kyun-Seop, Lim, Hyeong-Seok, MD, PhD
Format: Article
Language:English
Subjects:
Administration, Oral
Adult
Biological and medical sciences
Blood
Carbonic Anhydrase Inhibitors - administration & dosage
Carbonic Anhydrase Inhibitors - adverse effects
Carbonic Anhydrase Inhibitors - pharmacokinetics
CG100649
COX-2 inhibitor
Cross-Over Studies
Cyclooxygenase 2 Inhibitors - administration & dosage
Cyclooxygenase 2 Inhibitors - adverse effects
Cyclooxygenase 2 Inhibitors - pharmacokinetics
Cytochrome P-450 CYP3A Inhibitors
Drug Administration Schedule
Drug dosages
drug interaction
Drug Synergism
Drug therapy
Enzymes
Heart attacks
Hepatitis
Humans
Internal Medicine
ketoconazole
Ketoconazole - administration & dosage
Ketoconazole - adverse effects
Laboratories
Male
Medical Education
Medical sciences
Middle Aged
pharmacokinetic
Pharmacology. Drug treatments
Studies
Young Adult
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Summary: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. Objectives 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. Conclusion 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. ClinicalTrials.gov identifier: NCT01154764.
ISSN:0149-2918
1879-114X
DOI:10.1016/j.clinthera.2013.12.004