title: Predicting drug candidate victims of drug-drug interactions, using microdosing.
abstract: OBJECTIVE
  The aim of this crossover human male volunteer study was to investigate the utility of microdosing in the investigation of drug-drug interactions.
  
  
  METHODS
  A mixture of midazolam, tolbutamide, caffeine and fexofenadine were administered as a microdose (25 μg each) before and after administration of a combined pharmacological dose of ketoconazole (400 mg) and fluvoxamine (100 mg) to inhibit P-glycoprotein and metabolism by cytochrome P450 (CYP) 1A2, CYP3A4 and CYP2C9.
  
  
  RESULTS
  When administered alone, pharmacokinetics for all four microdosed compounds scaled well with those reported for therapeutic doses and with previously performed microdose studies. The pharmacokinetics of each compound administered as a microdose were significantly altered after the administration of ketoconazole and fluvoxamine, showing statistically significant (p < 0.01) 12.8-, 8.1- and 3.2-fold increases in the area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) for midazolam, caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC(∞) was observed for tolbutamide. The changes in pharmacokinetics mediated by ketoconazole and fluvoxamine were quantitatively consistent with previously reported, non-microdose, drug-drug interaction data from studies including the same compounds.
  
  
  CONCLUSIONS
  The initial data reported here demonstrate the utility of microdosing to investigate the risk of development drugs being victims of drug-drug interactions.
authors.affiliation: Xceleron Ltd, Innovation Way, York, UK. marie.croft@xceleron.com
authors.forename: Marie
authors.initials: M
authors.lastname: Croft
authors.forename: Brendan
authors.initials: B
authors.lastname: Keely
authors.forename: Ian
authors.initials: I
authors.lastname: Morris
authors.forename: Lan
authors.initials: L
authors.lastname: Tann
authors.forename: Graham
authors.initials: G
authors.lastname: Lappin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D016666:Fluvoxamine; D007654:Ketoconazole