Predicting Drug Candidate Victims of Drug-Drug Interactions, using Microdosing

A crossover study in healthy male volunteers tested whether microdosing (25 μg each of midazolam, tolbutamide, caffeine, and fexofenadine) can detect drug-drug interactions. After administering pharmacological doses of ketoconazole (400 mg) and fluvoxamine (100 mg) to inhibit key metabolic enzymes and transporters, the microdosed compounds showed significant pharmacokinetic changes: area under the curve increased 12.8-fold for midazolam, 8.1-fold for caffeine, and 3.2-fold for fexofenadine (all p < 0.01), and 1.8-fold (not significant) for tolbutamide. These changes matched those reported in conventional drug-drug interaction studies, demonstrating microdosing's utility for assessing whether development drugs are victims of interactions.

Study at a glance

Abstract

ObjectiveThe aim of this crossover human male volunteer study was to investigate the utility of microdosing in the investigation of drug-drug interactions.MethodsA 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.ResultsWhen 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.ConclusionThe initial data reported here demonstrate the utility of microdosing to investigate the risk of development drugs being victims of drug-drug interactions.