MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of...

Area of Science:

• Biomedical Informatics
• Pharmacology
• Drug Safety

Background:

• The U.S. Food and Drug Administration (FDA) issued a black box warning for metoclopramide (MCP) in 2009 due to increased risks of tardive dyskinesia (TD).
• Identifying strategies to mitigate MCP-induced TD is crucial for patient safety and effective treatment.

Purpose of the Study:

• To develop and validate a multi-step biomedical informatics screening (MSBIS) approach for identifying drugs that mitigate MCP-induced TD.
• To leverage publicly available bioactivity and drug safety data for drug repurposing and combination therapy design.

Main Methods:

• The MSBIS approach integrates TargetSearch bioinformatics scoring, FDA Adverse Event Reporting System (FAERS) analysis (unadjusted and adjusted odds ratios), and logistic regression.
• CHEMBL bioactivity data and FAERS data were utilized to assess drug anticholinergic activity and TD-mitigating effects.
• Statistical methods were employed to identify drugs with significant TD protective potential, controlling for confounding factors.

Main Results:

• Fentanyl emerged as the most promising drug candidate for mitigating MCP-induced TD, showing a significant protective effect (coefficient: -2.68; p-value<0.01).
• Clinical reports support fentanyl's efficacy, noting patient recovery from TD after fentanyl-induced general anesthesia.
• Loperamide was identified as a potent mitigating agent for a broader spectrum of drug-induced movement disorders via pharmacokinetic modifications.

Conclusions:

• The MSBIS approach is an efficient in silico tool for detecting unknown drug-drug interactions and designing combination therapies.
• This study demonstrates the potential of MSBIS for drug repurposing, specifically in addressing adverse drug reactions like TD.
• The findings highlight fentanyl and loperamide as potential therapeutic options for managing metoclopramide-induced TD and other movement disorders.