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

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Abstract

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 mg 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∞) 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.

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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Acknowledgements

This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), UK grant number BB/D525580/1. The clinical study was carried out at Simbec Research Limited (Merthyr Tydfil, UK). M. Croft and G. Lappin are employees of, and hold stock in, Xceleron Ltd, a company conducting commercial microdose studies. None of the other authors have any conflicts of interest.

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Authors and Affiliations

  1. York Biocentre, Innovation Way, Xceleron Ltd, Heslington, York, YO10 5NY, UK

    Marie Croft & Graham Lappin

  2. Department of Chemistry, University of York, York, UK

    Marie Croft & Brendan Keely

  3. Hull York Medical School, University of York, York, UK

    Ian Morris

  4. Simbec Research Limited, Merthyr Tydfil, UK

    Lan Tann

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  1. Marie Croft
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  2. Brendan Keely
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  3. Ian Morris
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  4. Lan Tann
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  5. Graham Lappin
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Correspondence to Marie Croft.

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Croft, M., Keely, B., Morris, I. et al. Predicting Drug Candidate Victims of Drug-Drug Interactions, using Microdosing. Clin Pharmacokinet 51, 237–246 (2012). https://doi.org/10.2165/11597070-000000000-00000

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