Pharmacokinetics II: 14 C-labelled microdosing in assessing drug pharmacokinetics at phase 0

Abstract

Microdosing came onto the scene with the first publication of data in 2003 (Lappin and Garner, Nat Rev Drug Discov 2(3):233-240, 2003). Since this time the number of compounds where the pharmacokinetics observed at a microdose compared to a therapeutic dose has grown steadily. Based upon the most up-todate review at the time of writing (2013, reference Lappin et al., Expert Opin Drug Metab Toxicol 9(7):817-834, 2013), there are 35 compounds where microdose and therapeutic dose pharmacokinetics can be compared (oral, intravenous, human and animal). Of these, 79 % showed scalable pharmacokinetics between a microdose and a therapeutic dose when administered orally and 100 % when administered intravenously (scalable is defined as the pharmacokinetics being within a factor of 2). Where pharmacokinetic non-linearity is seen, a growing understanding of the mechanisms involved is being applied to interpret the microdose data in the context of the selection of candidate drugs for further development. Inclusion of a 14 C isotopic tracer into the molecule enables sensitive AMS analysis to be used, obtaining an early indication of the drug's metabolism in humans.