title: In silico evaluation of warfarin-bucolome therapy.
abstract: OBJECTIVE
  Some reports have suggested that bucolome, an inhibitor of cytochrome P450 2C9, is useful for decreasing inter-patient variation in warfarin clearance. The purpose of the present study was to evaluate the utility of the concomitant administration of bucolome and warfarin using an in silico approach.
  
  
  METHODS
  In vitro data regarding the enzymatic kinetics of (S)-warfarin and bucolome were collected from the literature. As a validation study, the geometric mean (GM) of the oral unbound clearance of (S)-warfarin and its inter-patient variation (assessed using the standard deviation of its natural logarithm (σ)) were predicted using a physiologically based population pharmacokinetic simulator (Simcyp(TM) ) and compared with clinical data. The utility of the concomitant administration was evaluated by comparing the GM and σ values predicted under various conditions (the prediction study).
  
  
  CONCLUSIONS
  The σ values in the presence and absence of bucolome were predicted to be 0.73 and 0.68, respectively, suggesting that bucolome might increase the inter-patient variation, as clinically observed. In the prediction study, the σ value of the bucolome co-administered group was greater in almost all of the examined conditions. In conclusion, the concomitant administration of bucolome might not be useful for reducing the inter-patient variation of (S)-warfarin pharmacokinetics. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Division of Clinical Pharmacy, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.affiliation: Division of Clinical Pharmacy, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hakoda
authors.affiliation: Division of Clinical Pharmacy, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Imaoka
authors.affiliation: Division of Clinical Pharmacy, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Akiyoshi
mesh_terms: D000925:Anticoagulants / Q000493:pharmacokinetics*; D001463:Barbiturates / Q000494:pharmacology*; D003198:Computer Simulation; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D001463:Barbiturates; D065688:Cytochrome P-450 CYP2C9 Inhibitors; D014859:Warfarin; D015725:Fluconazole; C084817:bucolome
keywords: CYP2C9; DDI; bucolomel; warfarin