Tham, L.; Goh, B.; Wang, L.; Yong, W.; Wong, C.; Lee, S.; Soo, R.; Sukri, N.; Lee, H. S.
February 2006
Clinical Pharmacology & Therapeutics;Feb2006, Vol. 79 Issue 2, pP23
Academic Journal
Background/aims: Midazolam (MDZ) clearance (CL) has shown correlation with docetaxel (DOC) CL. This study compared MDZ-phenotyping of DOC CL with and without keotconazole (KETO) inhibition of CYP3A.Methods: In this open-label study, the pharmacokinetics of MDZ and DOC and their correlations were compared with (n = 45) and without KETO inhibition (n= 33). DOC and MDZ doses for the control versus KETO-modulated group were 75-100mg/m2 versus 16.5-70mg and IV 2.5mg versus 1mg respectively. Plasma-concentrations time-profiles were analyzed by noncompartmental method. Main OH-metabolites:parent ratios for MDZ and DOC were examined to confirm CYP3A inhibition.Results: Mean MDZ CL showed a 6-fold reduction in CL with KETO and significance for variance reduction (p<0.0001). 1'OH MDZ/MDZ ratios were highly significant (p<0.0001) with control being 11.8 (15 mins), 10.9 (1h), 11.1 (2h) and 10.2 (5h) times higher. Mean DOC CL showed a 1.8-fold reduction but not its variance (p=0.179). The metabolite ratios of M4/DOC and M1+M3/DOC were 2.4 (p< 0.001) and 1.7 (p = 0.005) times higher with control, at 1h, and 2.7 (p = 0.015) and 1.5 (p = 0.684) times higher at 2h. Correlation between MDZ and DOC CLs was lost in the ketoconazole group (r = 0.184, p = 0.263) but modest correlation was found with creatinine CL (r=0.484, p=0.002) instead.Conclusions: KETO reduced MDZ and DOC CLs to different extents. MDZ CL became more predictable but DOC CL remained highly variable. MDZ is unsuitable for phenotyping DOC under KETO-modulation.Clinical Pharmacology & Therapeutics (2005) 79, P23–P23; doi: 10.1016/j.clpt.2005.12.083


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