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PI‐62
Author(s) -
Tham L.,
Goh B.,
Wang L.,
Yong W.,
Wong C.,
Lee S.,
Soo R.,
Sukri N.,
Lee H. S.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.083
Subject(s) - pharmacokinetics , chemistry , metabolite , midazolam , cyp3a , docetaxel , pharmacology , medicine , metabolism , biochemistry , cytochrome p450 , chemotherapy , sedation
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/m 2 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