Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development

Because three out of four drug candidates fail in clinical trials, and because costs and pressure to reduce animal experiments are rising, there is a need for better early human screening. Positron emission tomography (PET) allows non-invasive measurement of drug distribution and concentration in the human body when the drug is labeled with a positron-emitting radionuclide without altering its biochemical properties. Recent advances in rapid synthesis of labeled compounds enable many new drug candidates to be used as PET probes. The authors propose that early PET-microdosing studies, using very low drug doses, can help select or reject compounds based on human in vivo performance.

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Abstract

The realisation that new chemical entities under development as drug candidates fail in three of four cases in clinical trials, together with increased costs and increased demands of reducing preclinical animal experiments, have promoted concepts for improvement of early screening procedures in humans. Positron emission tomography (PET) is a non-invasive imaging technology, which makes it possible to determine drug distribution and concentration in vivo in man with the drug labelled with a positron-emitting radionuclide that does not change the biochemical properties. Recently, developments in the field of rapid synthesis of organic compounds labelled with positron-emitting radionuclides have allowed a substantial number of new drug candidates to be labelled and potentially used as probes in PET studies. Together, these factors led to the logical conclusion that early PET studies, performed with very low drug doses-PET-microdosing-could be included in the drug development process as one means for selection or rejection of compounds based on performance in vivo in man. Another important option of PET, to evaluate drug interaction with a target, utilising a PET tracer specific for this target, necessitates a more rapid development of such PET methodology and validations in humans. Since only very low amounts of drugs are used in PET-microdosing studies, the safety requirements should be reduced relative to the safety requirements needed for therapeutic doses. In the following, a methodological scrutinising of the concept is presented. A complete pre-clinical package including limited toxicity assessment is proposed as a base for the regulatory framework of the PET-microdosing concept.