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In Vitro Approach to Assess the Potential for Risk of Idiosyncratic Adverse Reactions Caused by Candidate Drugs

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†̂ DMPK Innovative Medicine, AstraZeneca, Mölndal, 431 83, Sweden
Discovery DMPK, AstraZeneca, Wilmington, Delaware, United States
§ DMPK Innovative Medicine, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
# Discovery DMPK, AstraZeneca, Loughborough, Leicestershire LE11 5RH, United Kingdom
*Tel: +46 31 776 25 67. E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2012, 25, 8, 1616–1632
Publication Date (Web):May 31, 2012
Copyright © 2012 American Chemical Society

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    Idiosyncratic adverse drug reactions (IADRs) in humans can result in a broad range of clinically significant toxicities leading to attrition during drug development as well as postlicensing withdrawal or labeling. IADRs arise from both drug and patient related mechanisms and risk factors. Drug related risk factors, resulting from parent compound or metabolites, may involve multiple contributory mechanisms including organelle toxicity, effects related to compound disposition, and/or immune activation. In the current study, we evaluate an in vitro approach, which explored both cellular effects and covalent binding (CVB) to assess IADR risks for drug candidates using 36 drugs which caused different patterns and severities of IADRs in humans. The cellular effects were tested in an in vitro Panel of five assays which quantified (1) toxicity to THLE cells (SV40 T-antigen-immortalized human liver epithelial cells), which do not express P450s, (2) toxicity to a THLE cell line which selectively expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and galactose media, which is indicative of mitochondrial injury, (4) inhibition of the human bile salt export pump, BSEP, and (5) inhibition of the rat multidrug resistance associated protein 2, Mrp2. In addition, the CVB Burden was estimated by determining the CVB of radiolabeled compound to human hepatocytes and factoring in both the maximum prescribed daily dose and the fraction of metabolism leading to CVB. Combining the aggregated results from the in vitro Panel assays with the CVB Burden data discriminated, with high specificity (78%) and sensitivity (100%), between 27 drugs, which had severe or marked IADR concern, and 9 drugs, which had low IADR concern, we propose that this integrated approach has the potential to enable selection of drug candidates with reduced propensity to cause IADRs in humans.

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    Structures and maximum daily doses in μmol; replicates and confidence intervals for all compounds in the Mrp2, BSEP, MitoTox, THLE-Null, and THLE-3A4 assays; data analysis of aggregated in vitro Panel scores and levels of IADR concern; and plot of the aggregated in vitro Panel score vs maximum daily dose. This material is available free of charge via the Internet at

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