Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide.
OBJECTIVE
Dexloxiglumide is a new CCK(1) receptor antagonist under investigation for treatment of functional gastrointestinal disorders and is metabolized by CYP3A4 and CYP2C9. The objectives of these two separate randomized, two-period, two-treatment crossover studies were to investigate the effects of steady-state ketoconazole, a model CYP3A4 inhibitor (Study 1), and steady-state fluconazole, a model CYP2C9 inhibitor (Study 2), on the pharmacokinetics of dexloxiglumide in healthy subjects.


METHODS
Plasma samples were analysed for dexloxiglumide and its primary metabolites: O-demethyl dexloxiglumide (ODM; Study 1 and 2) and dexloxiglumide carboxylic acid (DCA; Study 2).


RESULTS
Following ketoconazole coadministration, dexloxiglumide C(max) increased by 32% (90% confidence intervals (CI) 112-154), with unchanged ODM C(max); AUC of dexloxiglumide and ODM increased by 36% (90% CI 124-140 and 128-142, respectively). No changes were observed in dexloxiglumide or ODM t((1/2)). Fluconazole coadministration caused a 77% increase (90% CI 154-204) in dexloxiglumide C(max), no change in ODM C(max) and a 32% decrease (90% CI 62-75) in DCA C(max). Fluconazole coadministration resulted in a 2.5-fold increase (90% CI 235-267) in dexloxiglumide AUC, 40% increase (90% CI 136-156) in ODM AUC and an 18% decrease (90% CI 82-94) in DCA AUC. The t((1/2)) of all three analytes increased by approximately 2-fold with fluconazole coadministration (P-value < 0.05).


CONCLUSIONS
Ketoconazole caused a minimal increase while fluconazole caused a moderate increase in dexloxiglumide systemic exposure with no change in the adverse event profile of dexloxiglumide.
Jakate
Abhijeet S
AS
Department of Clinical Pharmacology and Drug Dynamics, Forest Research Institute, Harborside Financial Center Plaza V, Jersey City, NJ 07311, USA.
Roy
Partha
P
Patel
Alpita
A
Abramowitz
Wattanaporn
W
Persiani
Stefano
S
Wangsa
Julie
J
Kapil
Ram
R
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004338:Drug Combinations; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010421:Pentanoic Acids / Q000097:blood / Q000493:pharmacokinetics*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013997:Time Factors
D000935:Antifungal Agents; D004338:Drug Combinations; D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; C103490:dexloxiglumide; D015725:Fluconazole; D007654:Ketoconazole