posted on 2012-08-20, 00:00authored byRichard A. Thompson, Emre M. Isin, Yan Li, Lars Weidolf, Ken Page, Ian Wilson, Steve Swallow, Brian Middleton, Simone Stahl, Alison
J. Foster, Hugues Dolgos, Richard Weaver, J. Gerry Kenna
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.