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Human absorption, distribution, metabolism and excretion (hADME) studies with 14C- or 3H-labeled drug have provided answers to critical drug development questions since many years. These include the balance of dose recovered versus dose administered, the drug’s metabolic fate, and elimination routes for parent drug and metabolites. Historically, hADME studies deploy a single dose design, with collection of blood, urine, feces, and possibly expired air samples for a predefined period of time (see e.g. Ramamoorthy et al., 2022). This 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. In our presentation, we will address the designs as proposed in the FDA Guidance for Human Radiolabeled Mass Balance Studies and discuss their application, i.e., single radiolabeled dose, or single radiolabeled dose preceded by and on top of repeated dosing of unlabeled, ‘cold’ drug alone, and compare these to repeated oral dosing of radiolabeled drug.
Key take-aways: - Single-dose designs for human ADME studies are suitable in case of linear and time-independent PK. - An alternative design, with administration of a single dose of radiolabeled drug after repeated dosing with unlabeled drug up to steady state, should be considered in case of non-linear and/or time-dependent PK. - Designs involving repeated dosing with radiolabeled drug up to steady state have been employed in selected cases, but pros and con versus the above designs remain to be confirmed.
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