ADME studies are conducted to define clearance routes and (ultimately) to demonstrate metabolic relevance of the safety assessment (toxicity) studies conducted in animals when extrapolating the safety data to humans.

 

They are conducted using radiolabelled test item (typically 14C isotope) and so require considerable advance planning.

 

ADME studies (generally single-dose) are typically conducted in a rodent and non-rodent model which should be the same species as selected for safety assessment and selected based upon:

 

i) similar in vitro hepatocyte metabolite profiles vs human (accounting for known MIST alerts) 

ii) sometimes relevant pharmacological model

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AIMS:

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+ To confirm the major clearance routes of drug from animal species used in safety assessment

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+ To confirm drug pharmacokinetics and distribution in animal species

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+ To identify and quantify the major drug metabolites formed by animal species (essential to ensure relevance of extrapolating safety-related animal data to human, in compliance with FDA MIST guidance  (see my Resource page for direct link to the latest FDA MIST guidance, March 2020)

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COMPONENTS:

 

+ Mass Balance: Recovery of Radioactivity + Rates and Routes of Excretion 

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+ Distribution: Tissue analysis: QWBA (sometimes combustion)

 

+ Metabolite Profiling: plasma, faces and urine

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+ Metabolite Identification: High resolution, accurate mass spectrometry

 

+ Quantification of metabolites: define routes of excretion

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