Off target toxicities and links with physicochemical properties of medicinal products, including antibiotics, oligonucleotides, lipid nanoparticles (with cationic and/or anionic charges). Data review suggests an emerging pattern.

Toxicology is an essential part of any drug development plan. Circumnavigating the risk of failure because of a toxicity issue can be a challenge, and failure in late development is extremely costly. To identify potential risks, it requires more than just understanding the biological target. The toxicologist needs to consider a compound's structure, it's physicochemical properties (including the impact of the overall formulation), as well as the biological target (e.g., receptor interactions). Understanding the impact of the physicochemical properties can be used to predict potential toxicities in advance by incorporating key endpoints in early screening strategies and/or used to compare toxicity profiles across lead candidates. This review discussed the risks of off-target and/or non-specific toxicities that may be associated with the physicochemical properties of compounds, especially those carrying dominant positive or negative charges, including amphiphilic small molecules, peptides, oligonucleotides and lipids/liposomes/lipid nanoparticles. The latter of which are being seen more and more in drug development, including the recent Covid pandemic, where mRNA and lipid nanoparticle technology is playing more of a role in vaccine development. The translation between non-clinical and clinical data is also considered, questioning how a physicochemical driven toxicity may be more universal across species, which means that such toxicity may be reassuringly translatable between species and as such, this information may also be considered as a support to the 3 R's, particularly in the early screening stages of a drug development plan.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sarah Gould reports a relationship with Charles River Laboratories that includes: employment.
(Copyright © 2023. Published by Elsevier B.V.)