The Consultancy Activity on In Silico Models for Genotoxic Prediction of Pharmaceutical Impurities

Abstract

The toxicological assessment of DNA-reactive/mutagenic or clastogenic impurities plays an important role in the regulatory process for pharmaceuticals; in this context, in silico structure-based approaches are applied as primary tools for the evaluation of the mutagenic potential of the drug impurities. The general recommendations regarding such use of in silico methods are provided in the recent ICH M7 guideline stating that computational (in silico) toxicology assessment should be performed using two (Q)SAR prediction methodologies complementing each other: a statistical-based method and an expert rule-based method.Based on our consultant experience, we describe here a framework for in silico assessment of mutagenic potential of drug impurities. Two main applications of in silico methods are presented: (1) support and optimization of drug synthesis processes by providing early indication of potential genotoxic impurities and (2) regulatory evaluation of genotoxic potential of impurities in compliance with the ICH M7 guideline. Some critical case studies are also discussed.

A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities

“…Currently, it is recognized that a successful drug is determined not only by better efficacy but also by acceptable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, leading to various in vitro high-throughput ADMET screening established in the early stages of drug discovery, which help reduce the cost of drug development and the number of safety problems ( Merlot, 2010 ; Moroy et al, 2012 ). Structure–activity/toxicity relationship has been employed to investigate ADMET properties and predict toxicity in silico ( Greene et al, 2015 ; Pavan et al, 2016 ; Guan et al, 2019 ). In addition, our recent studies have shown that structure–toxicity relationship combined with ADMET parameters evaluation and molecular docking (structure-based computations) can be used to predict drug impurity toxicity in silico ( Han et al, 2017 ; Han et al, 2018a ; Han et al, 2018b ; Han et al, 2019 ).…”

In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities

“…The toxicity of drug impurities is closely related to their structure. Structure-activity relationships (SARs) have been widely used in Europe and the United States to predict toxicity by computer (Greene et al, 2015; Pavan et al, 2016; Guan et al, 2019). We have recently systematically discussed the structure-toxicity relationship of cephalosporins via the zebrafish embryo toxicity test combined with computational chemistry and molecular docking techniques.…”