Thursday, January 9, 2014
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In silico prediction of drug toxicity based on effective
A logistic regression model
based on effective plasma concentration (Ceff) of a compound
could provide an in silico measure for predicting toxicity. In
silico analysis compared the physicochemical and pharmacological
characteristics of 56 compounds that had advanced to preclinical exploratory
toxicology studies (ETS) and were classified as 'pass' or 'fail' for toxicity
based on therapeutic index ratios from in vivo studies. ETS pass
outcomes correlated significantly with Ceff values lower
than 250 nM
for total drug (p<0.0001) and 40 nM for free drug (p=0.0532).
In logistic regression analysis, a Ceff of 1 nM for total
drug yielded over 80% probability of success for an ETS pass outcome, whereas
a Ceff of 1 mm yielded 20%
probability of success. Next steps could include expanding the model to
incorporate in vitro cell-based assay data and other less expensive in
vivo screening data endpoints.
Published online Jan. 9, 2014
Patent and licensing status
Wager, T.T. et al. J.
Med. Chem.; published online Nov. 12, 2013;
Contact: Travis T. Wager, Pfizer Worldwide Research and
Development, Cambridge, Mass.
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