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PIII‐55
Author(s) -
Quinney S. K.,
Gorski J. C.,
Lucksiri A.,
Zhang X.,
Chien J. Y.,
Jones D. R.,
Hall S. D.
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.2005.12.263
Subject(s) - physiologically based pharmacokinetic modelling , chemistry , pharmacokinetics , midazolam , pharmacology , cyp3a4 , cyp3a , drug interaction , in vitro , microsome , cytochrome p450 , biochemistry , metabolism , medicine , sedation
BACKGROUND The scale‐up of in vitro data to estimate drug‐drug interactions is problematic for mechanism‐based inhibitors, such as clarithromycin (CLAR), because of inherently nonlinear disposition. METHODS A physiologically‐based pharmacokinetic (PBPK) model for the interaction between midazolam (MDZ) and CLAR including mechanism‐based and competitive inhibition of CYP3A4 was developed from published reports using Trial Simulator™ (Pharsight). k inact and K I for CLAR and 14‐hydroxyCLAR (14OHC) were determined by in vitro preincubation studies using cDNA‐expressed CYP3A4(+b5) and 6β‐hydroxytestosterone formation as a measure of CYP3A activity. Concentration‐time data was generated for MDZ, CLAR and its 14‐hydroxy and N‐desmethyl metabolites. RESULTS k inact and K I for CLAR were 4.32 h −1 and 5.5 μM. k inact was 3 h −1 for 14OHC and K I was set at 5.5 μM. The nonlinear relationship between dose (100–800 mg) and CLAR and 14OHC AUC were predicted. A simulated study of 500 mg CLAR BID for 7 days orally with intravenous (IV) or oral MDZ administered before and 7, 9, 11 and 14 days after start of CLAR dosing, accurately predicted the disposition of MDZ, CLAR and its metabolites in a study previously conducted by our group. The predicted AUC‐ratio of MDZ (day 7/before) following IV and oral dosing was 2.6 and 6.9, consistent with the observed ratios of 2.1 and 7.4, respectively. CONCLUSIONS The nonlinear pharmacokinetics of CLAR and its interaction with MDZ were predicted based on in vitro data using a PBPK model. Clinical Pharmacology & Therapeutics (2005) 79 , P73–P73; doi: 10.1016/j.clpt.2005.12.263