PI-013 - CONSIDERATIONS ON HUMAN ADME STUDIES AND PROPOSED DECISION TREE TOWARDS TAILORED STUDY DESIGNS.

K. Mirdamadi¹, J. Hartstra², E. Van Hoogdalem³, A. Roffel²; ¹ICON plc, ICON plc - Montreal, Canada, ²ICON plc, ICON plc - Groningen, The Netherlands, ³ICON plc, ICON plc - Leiden, The Netherlands.

Background: Human absorption, distribution, metabolism and excretion (hADME) studies with 14C- or 3H-labeled drug provide answers to various critical development questions, including the balance of dose recovered versus dose administered, the drug’s metabolic fate, and elimination routes for parent drug and metabolite(s), thereby informing the drug’s further development strategy. The classical hADME study design deploys a single, pharmacologically relevant dose of drug containing a tracer (1.85-3.7 MBq) or a microtracer amount (0.01-0.1 MBq) of 14C-labeled drug, followed by collection of blood, urine, faeces, and – in specific cases – sampling of expired air, with monitoring of safety and tolerability. The classical design proved adequate in many cases, but it may not be adequate in specific cases when single-dose data cannot be extrapolated to clinical use with (sub)-chronic dosing of drug, e.g. for drugs showing auto-induction or -inhibition, with limited dissolution or saturable transport, with non-linear pharmacokinetics, or when slow accumulation of parent drug or metabolite(s) is expected.

Methods: To address these latter cases, tailored designs have been explored and published, e.g. with a single oral tracer dose preceded by, and on top of repeated dosing of ‘cold’ drug alone, or preceded by repeated oral dosing of ‘cold’ drug with a microtracer dose.

Results: These tailored designs appear very appropriate to accommodate drugs with slow metabolism and elimination, and for which the classical design with a single dose only may not be appropriate. This is with the note that understanding the benefit of designs with repeated dosing of microtracer labeled ‘cold’ drug may require more experience.

Conclusion: To collect further clinical experience with tailored hADME study designs, ICON proposes the attached decision tree, taking into account concerns on extrapolating single dose data to (sub)-chronic use, and considering bioanalytical requirements versus availability of accelerated mass spectrometry (AMS) in addition to mass spectrometry and liquid scintillation counting (LSC).