Microdosing Phase 0

Sub-pharmacological human microdosing studies (Phase 0) provide accurate predictive human PK/ADME data (compared to allometry) for many new drug candidates, i.e. the best model of human is human. This data de-risks the best candidates to succeed in Phase I clinical development. Microdosing is also useful to assess absorption and systemic exposure, such as skin and lung.

In Phase 0 clinical designs, we recommend that the microdose is given both oral and IV in a cross-over design, to provide data on disposition PK and absolute bioavailability.

Pharmaron supports microdosing studies with both stable and radiolabels:

• Using ¹³C drug with LC-MS/MS analysis (assuming the assay can reach the desired LLOQ)
• Using ¹⁴C drug with LC+AMS analysis (typically achieves lower LLOQ’s than LC-MS/MS with more rapid method development and validation timelines)

Typical applications:

• Lead and backup compound selection
• Comparator studies with existing marketed drug(s)
• Drug-drug interaction (DDI) studies using cassette microdosing techniques with probe substrates (for enzyme inhibition/induction)
• Combination ¹⁴C microdose - ¹¹C PET PK/PD studies, for CNS compounds
• Drug targeting and tissue disposition (e.g. anti-cancer chelating agents in human DNA from tumor biopsies)