Phase 0/Microdosing Approaches: Time for Mainstream Application in Drug Development
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Phase 0 approaches — which include microdosing — evaluate subtherapeutic exposures of new drugs in first-in-human studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Indeed, phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more accurate developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be considered for application in current drug development scenarios.
Reducing attrition in clinical development is the single most important challenge in increasing pharmaceutical industry productivity. A key strategy to reducing attrition rates is to improve the quality of candidates entering clinical development. A phase 0 stage, so named because it is positioned between preclinical and phase I stages (Table 1), has the potential to improve preclinical candidate selection by applying approaches such as subtherapeutic microdosing (100 µg or less) to provide human in vivo data on pharmacokinetics, pharmacodynamics and target engagement earlier in the development process than with traditional approaches. Phase 0 approaches also have the potential to provide data that is not readily acquired via traditional approaches. These include first-in-human testing in patients, simultaneous testing of multiple drug candidates (known as cassette microdosing), intravenous administration of oral drugs and intratarget microdosing (ITM; the administration of microdoses locally to generate momentarily therapeutic level exposures in targets of interest). These advantages allow triaging of preclinical candidates for entry into clinical development in a more informed, timely and effective manner. Overall, this webinar will provide state-of-the-art perspective on phase 0 drug development strategies and their utility in improving therapeutic development and reducing clinical candidate attrition rates.