Integrated systems pharmacology analysis of clinical drug-induced peripheral neuropathy.
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.
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
J
J
Hur
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, USA.
A Y
AY
Guo
Department of Statistics, University of Wisconsin, Madison, Wisconsin, USA.
W Y
WY
Loh
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
E L
EL
Feldman
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
J P F
JP
Bai