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CPT Pharmacometrics Syst Pharmacol. 2014 May 14;3:e114. doi: 10.1038/psp.2014.11.

Integrated systems pharmacology analysis of clinical drug-induced peripheral neuropathy.

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Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, USA.
Department of Statistics, University of Wisconsin, Madison, Wisconsin, USA.
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.


A systems pharmacology approach was undertaken to define and identify the proteins/genes significantly associated with clinical incidence and severity of drug-induced peripheral neuropathy (DIPN). Pharmacological networks of 234 DIPN drugs, their known targets (both intended and unintended), and the intermediator proteins/genes interacting with these drugs via their known targets were examined. A permutation test identified 230 DIPN-associated intermediators that were enriched with apoptosis and stress response genes. Neuropathy incidence and severity were curated from drug labels and literature and were used to build a predictive model of DIPN using a regression tree algorithm, based on the drug targets and their intermediators. DIPN drugs whose targets interacted with both v-myc avian myelocytomatosis viral oncogene homolog (MYC) and proliferating cell nuclear antigen-associated factor (PAF15) were associated with a neuropathy incidence of 38.1%, whereas drugs interacting only with MYC had an incidence of 2.9%. These results warrant further investigation in order to develop a predictive tool for the DIPN potential of a new drug.

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