Phase 0 microdose trials are exploratory studies to early assess human pharmacokinetics of new chemical entities, while limiting drug exposure and risks for participants. The microdose concept is based on the assumption that microdose pharmacokinetics can be extrapolated to pharmacokinetics of a therapeutic dose. However, it is unknown whether microdose pharmacokinetics are actually indicative of the pharmacokinetics at therapeutic dose. The aim of this review is to investigate the predictive value of microdose pharmacokinetics and to identify drug characteristics that may influence the scalability of these parameters. The predictive value of microdose pharmacokinetics was determined for 46 compounds and showed adequate predictability for 28 of 41 orally administered drugs (68%) and 15 of 16 intravenously administered drugs (94%). Microdose pharmacokinetics were considered predictive if the mean observed values of the microdose and the therapeutic dose were within twofold. Nonlinearity may be caused by saturation of enzyme and transporter systems, such as intestinal and hepatic efflux and uptake transporters. The high degree of success regarding linear pharmacokinetics shows that phase 0 microdose trials can be used as an early human model for determination of drug pharmacokinetics.
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