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

Full content URL: http://dx.doi.org/10.2165/11597070-000000000-00000

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Abstract

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 interactions

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

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