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

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Publication details

JournalClinical pharmacokinetics
DatePublished - 2012
Issue number4
Number of pages10
Pages (from-to)237-246
Original languageEnglish


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 micro-dose (25 mu g 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(infinity)) for midazolam, caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC(infinity) 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 interactions.

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