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

Croft, Marie, Keely, Brendan, Moss, Ian , Tann, Lan and Lappin, Graham (2012) Predicting drug candidate victims of drug-drug interactions, using microdosing. Clinical Pharmacokinetics, 51 (4). pp. 237-246. ISSN 0312-5963

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The aim of this crossover human ale volunteer study was to investigate the utility of microdosing
in the investigation of drug-drug interactions.
A mixture of midazolam, tolbutamide, caffeine and fexofenadine were administered as a micro-
dose (25
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.
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
) for midazolam,
caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC
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.
The initial data reported here demonstrate the utility of microdosing to investigate the risk of
development drugs being victims of drug-drug interactions

Keywords:Microdosing, Drug interactions, Drug delivery, bmjpdf
Subjects:B Subjects allied to Medicine > B230 Pharmacy
Divisions:College of Science > School of Pharmacy
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ID Code:7348
Deposited On:28 Feb 2013 15:27

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