AIMS: To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP)3A4, on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. METHODS: In this randomized, double-blind, cross-over trial 10 healthy male subjects received either itraconazole 200 mg or matched placebo once daily for 4 days. On day 4, a single 0.5 mg dose of brotizolam was administered orally. Plasma concentrations of brotizolam were followed up to 24 h, together with assessment of psychomotor function measured by the digit symbol substitution test (DSST), visual analogue scales and UKU side-effect rating scale. RESULTS:Itraconazole significantly (P < 0.001) decreased the apparent oral clearance (CL/F) (16.47 +/- 4.3 vs 3.91 +/- 2.1), increased the area under the concentration-time curves (AUC) from 0 h to 24 h (28.37 +/- 10.8 vs 68.71 +/- 24.1 ng ml h(-1)), and prolonged the elimination half-life (4.56 +/- 1.4 vs 23.27 +/- 10.3 h) of brotizolam. The AUC(0,24 h) of the DSST (P < 0.001) and the item 'sleepiness' of UKU (P < 0.05) were significantly decreased. CONCLUSIONS:Itraconazole increases plasma concentrations of brotizolam probably via its inhibitory effect on CYP3A4 brotizolam metabolism.
RCT Entities:
AIMS: To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP)3A4, on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. METHODS: In this randomized, double-blind, cross-over trial 10 healthy male subjects received either itraconazole 200 mg or matched placebo once daily for 4 days. On day 4, a single 0.5 mg dose of brotizolam was administered orally. Plasma concentrations of brotizolam were followed up to 24 h, together with assessment of psychomotor function measured by the digit symbol substitution test (DSST), visual analogue scales and UKU side-effect rating scale. RESULTS:Itraconazole significantly (P < 0.001) decreased the apparent oral clearance (CL/F) (16.47 +/- 4.3 vs 3.91 +/- 2.1), increased the area under the concentration-time curves (AUC) from 0 h to 24 h (28.37 +/- 10.8 vs 68.71 +/- 24.1 ng ml h(-1)), and prolonged the elimination half-life (4.56 +/- 1.4 vs 23.27 +/- 10.3 h) of brotizolam. The AUC(0,24 h) of the DSST (P < 0.001) and the item 'sleepiness' of UKU (P < 0.05) were significantly decreased. CONCLUSIONS:Itraconazole increases plasma concentrations of brotizolam probably via its inhibitory effect on CYP3A4brotizolam metabolism.
Authors: Jari J Lilja; Janne T Backman; Jouko Laitila; Harri Luurila; Pertti J Neuvonen Journal: Clin Pharmacol Ther Date: 2003-03 Impact factor: 6.875
Authors: T Miyama; H Takanaga; H Matsuo; K Yamano; K Yamamoto; T Iga; M Naito; T Tsuruo; H Ishizuka; Y Kawahara; Y Sawada Journal: Antimicrob Agents Chemother Date: 1998-07 Impact factor: 5.191