Predicting drug candidate victims of drug-drug interactions, using microdosing

Abstract Objective: The aim of this crossover human ale 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 micro- dose (25 m g each) before and after administration of a combined pharmacological dose of ketoconazole (400mg) and fluvoxamine (100mg) 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 pharmaco- kinetics of each compound administered as a microdose were significantly altered after the administration of ketoconazole andfluvoxamine, showing statistically significant (p < 0.01) 12.8-, 8.1- and3.2-fold increases in the area under the plasma concentration-time curve from time zero to infinity (AUC 1 ) for midazolam, caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC 1 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. Conclusion: The initial data reported here demonstrate the utility of microdosing to investigate the risk of development drugs being victims of drug-drug interaction