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Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential
journal contribution
posted on 2019-10-07, 16:34 authored by Michael
D. Aleo, Falgun Shah, Scott Allen, Hugh A. Barton, Chester Costales, Sarah Lazzaro, Louis Leung, Andrea Nilson, R. Scott Obach, A. David Rodrigues, Yvonne WillThe
hepatic risk matrix (HRM) was developed and used to differentiate
lead clinical and back-up drug candidates against competitor/marketed
drugs within the same pharmaceutical class for their potential to
cause human drug-induced liver injury (DILI). The hybrid HRM scoring
system blends physicochemical properties (Rule of Two Model: dose
and lipophilicity or Partition Model: dose, ionization state, lipophilicity,
and fractional carbon bond saturation) with common toxicity mechanisms
(cytotoxicity, mitochondrial dysfunction, and bile salt export pump
(BSEP) inhibition) that promote DILI. HRM scores are based on bracketed
safety margins (<1, 1–10, 10–100, and >100×
clinical Cmax,total). On the basis of
well-established clinical safety experience of marketed/withdrawn
drug candidates, the background analysis consists of 200 drugs from
the Liver Toxicity Knowledge Base annotated as Most-DILI- (79), Less-DILI-
(56), No-DILI- (47), and Ambiguous-DILI-concern (18) drugs. Scores
were generated for over 21 internal and 7 external drug candidates
discontinued for unacceptable incidence/magnitude of liver transaminase
elevations during clinical trials or withdrawn for liver injury severity.
Both hybrid scoring systems identified 70–80% Most-DILI-concern
drugs, but more importantly, stratified successful/unsuccessful drug
candidates for liver safety (incidence/severity of transaminase elevations
and approved drug labels). Incorporating other mechanisms (reactive
metabolite and cytotoxic metabolite generation and hepatic efflux
transport inhibition, other than BSEP) to the HRM had minimal beneficial
impact in DILI prediction/stratification. As is, the hybrid scoring
system was positioned for portfolio assessments to contrast DILI risk
potential of small molecule drug candidates in early clinical development.
This stratified approach for DILI prediction aided decisions regarding
drug candidate progression, follow-up mechanistic work, back-up selection,
clinical dose selection, and due diligence assessments in favor of
compounds with less implied clinical hepatotoxicity risk.
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Keywords
system blends physicochemical propertiesdrug candidateshepatic risk matrixdrug-induced liver injuryBinary Predictionsback-up drug candidatesbackground analysisBSEPcarbon bond saturationbracketed safety marginsmolecule drug candidatesreactive metabolitetoxicity mechanisms200 drugsDILI predictionliver transaminase elevationsdrug labelssafety experiencecytotoxic metabolite generationHRM scoresliver injury severitycontrast DILI riskliver safetydiligence assessmentsionization stateback-up selectionPartition Modelhepatotoxicity riskhepatic efflux transport inhibitionbile salt exportportfolio assessmentstransaminase elevationsHuman Drug-Induced Liver InjuryLiver Toxicity Knowledge Basedose selectiondrug candidate progressionmitochondrial dysfunction
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