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Big physics, small doses: the use of AMS and PET in human microdosing of development drugs

Nature Reviews Drug Discovery volume 2, pages 233–240 (2003)Cite this article

Abstract

The process of early clinical drug development has changed little over the past 20 years despite an up to 40% failure rate associated with inappropriate drug metabolism and pharmacokinetics of candidate molecules. A new method of obtaining human metabolism data known as microdosing has been developed which will permit smarter candidate selection by taking investigational drugs into humans earlier. Microdosing depends on the availability of two ultrasensitive 'big-physics' techniques: positron emission tomography (PET) can provide pharmacodynamic information, whereas accelerator mass spectrometry (AMS) provides pharmacokinetic information. Microdosing allows safer human studies as well as reducing the use of animals in preclinical toxicology.

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Figure 1: Schematic of conventional and microdose approaches to drug selection.
Figure 2: Semi-log plot comparing elimination of drug from plasma following a 5, 50 or 500 μg oral dose at a constant radioactive dose level of 50 nCi per subject.
Figure 3: Example of a drug metabolite profile from a plasma extract.
Figure 4: An example of uptake of 11C-labelled drugs into the human brain measured by positron emission tomography.

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Acknowledgements

We would like to thank Drs Ken Turteltaub and John Vogel at the Center for Acelerator Mass Spectrometry, Lawrence Livermore National Laboratories, USA, for introducing us to the AMS technique. Professors Bengt Langström and Mats Bergström at the PET Cenctre, Uppsala University, Sweden, for their assistance and for supplying Figure 4, and Dr Terry Jones, Manchester, UK, for his assistance on PET. In addition, the financial and scientific contributions of GlaxoSmithKline, Novartis, Pfizer, Janssen Pharmaceuticals and the University of York have proven invaluable to Xceleron Ltd.

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Authors and Affiliations

  1. the Head of Research and Development at Xceleron Ltd, York Biocentre, Innovation Way, Heslington, YO10 5NY, York, UK

    Graham Lappin

  2. the Chief Executive Officer at Xceleron Ltd, York Biocentre, Innovation Way, Heslington, YO10 5NY, York, UK

    R. Colin Garner

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Lappin, G., Garner, R. Big physics, small doses: the use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov 2, 233–240 (2003). https://doi.org/10.1038/nrd1037

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