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by John C Waterton on behalf of the TRISTAN Consortium

EMIM 2023

Abstract

Drugs and other xenobiotics are commonly eliminated via the liver. Uptake by the hepatocyte, and subsequent efflux, involves several transporters with different specificities. If a drug's  uptake is perturbed, a drug may be cleared less (or more) rapidly from the blood, leading to harmful overdosing or alternatively lack of efficacy.  Where one drug inhibits or enhances the uptake flux of a second drug, this is called a Drug-Drug Interaction (DDI).  DDIs can complicate the safe prescribing of medicines to patients who require different drugs which are substrates for the same transporter.  If its efflux is inhibited, harmful levels of drug may accumulate in the hepatocyte leading to drug-induced liver injury (DILI).

While hepatocyte uptake and efflux kinetics cannot be unambiguously determined from blood levels, imaging biomarkers from nuclear medicine or MR can provide more specificity (1).  Gadoxetate, a MR contrast agent with regulatory approval in most jurisdictions, has previously proved useful in this context.

Drug developers and regulatory authorities are very unlikely to rely on such imaging biomarkers unless they trust the acquisition, analysis and interpretation.  In particular they must be highly confident that an apparently negative finding ("drug does not perturb liver transporter fluxes") is a true indication of the drug's safety, and not an artefact of quirks in the methodology or irreproducibility between centres.  To address this, FDA established its biomarker qualification program (BQP) to provide confidence in the biomarker data in a specific context of use. Of note, of the 58 biomarkers listed in the qualification programme, a high proportion (31%) are imaging biomarkers and an equally high proportion (31%) are safety biomarkers, suggesting the importance of this route for imaging biomarkers of safety (i.e. lack-of-harm).