Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects

Phase 0/microdosing approaches: time for mainstream application in drug development?

“…Multiple preclinical candidates 11,12,97,[100][101][102][103][104]133 Selection using cassette microdosing 11 Microdosing study results and PBPK modelling combined to inform candidate selection 104 Conflicting or inadequate preclinical data Uncertainty in extrapolating pharmacokinetic and/or pharmacodynamic data from preclinical models to humans…”

“…It is obviously of value to obtain, as soon as possible, data in the stage most likely to lead to termination of development. Other methodological advantages over phase I approaches discussed later are the ability to test multiple candidates simultaneously in the same individuals (cassette microdosing), the ability to test enteric drugs by administering them parenterally and the use of methods such as ITM 11,13,16,28 .…”

“…Cassette microdosing is a method to assess drug disposition, including the potential for DDI (as 'victims' only), of multiple compounds administered simultaneously at microdose levels to research participants. Cassette microdosing can considerably reduce the variability, complexity, and costs of first-in-human studies 11,54,55,61,68,170,171 . Advances in liquid chromatography-tandem mass spectrometry technology, which nowadays offers high and ever-increasing sensitivity and resolution of test compounds and their metabolites in biological fluids, have considerably expanded the applications of cassette microdosing 58 .…”

“…Phase 0 approaches also have the potential to provide data that is not readily available with 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) [9][10][11][12][13][14][15][16][17][18] . These advantages allow triaging of preclinical candidates for entry into clinical Adoption of phase 0/microdosing approaches by drug developers has been limited by uncertainty about the impact of non-linearity on extrapolation from subtherapeutic to therapeutic-level exposures, the perception that only pharmacokinetic data can be obtained with these approaches and the concern that application of phase 0 approaches will lead to delays in developmental timelines 26,27 .…”

“…In addition, greater insight into non-linear mechanisms, their impact on extrapolation of subtherapeutic to therapeutic-level exposures and their management through modelling further increased the reliability and validity of extrapolation 29,33,[37][38][39][40] (discussed further later). In parallel, academic and commercial entities continued research into methods and applications 18, (Supplementary information A) to expand the effectiveness of these approaches, and sponsors have increasingly used phase 0 approaches in developmental scenarios not effectively addressed by traditional approaches [9][10][11][12][13][14]16,35,37,38,41, (Table 3; Supplementary information A).…”