Non-clinical studies required for new drug development - Part I: early in silico and in vitro studies, new target discovery and validation, proof of principles and robustness of animal studies

Abstract

This review presents a historical overview of drug discovery and the non-clinical stages of the drug development process, from initial target identification and validation, through in silico assays and high throughput screening (HTS), identification of leader molecules and their optimization, the selection of a candidate substance for clinical development, and the use of animal models during the early studies of proof-of-concept (or principle). This report also discusses the relevance of validated and predictive animal models selection, as well as the correct use of animal tests concerning the experimental design, execution and interpretation, which affect the reproducibility, quality and reliability of non-clinical studies necessary to translate to and support clinical studies. Collectively, improving these aspects will certainly contribute to the robustness of both scientific publications and the translation of new substances to clinical development.

Thermal Bioprinting Causes Ample Alterations of Expression of LUCAT1, IL6, CCL26, and NRN1L Genes and Massive Phosphorylation of Critical Oncogenic Drug Resistance Pathways in Breast Cancer Cells

“…In vitro testing for drug discovery keeps making strides, especially with the advancement of genomics, proteomics, pharmacodynamics, bioinformatics, and automated High Throughput Screening (Andrade et al, 2016;Peng et al, 2017). Target-based drug design using appropriate cell assays, has not only transformed the identification of new targets, but it has also been supplemented with virtual testing aka "in silico" testing.…”

“…Target-based drug design using appropriate cell assays, has not only transformed the identification of new targets, but it has also been supplemented with virtual testing aka "in silico" testing. With this approach, computer-based methods for drug simulations are utilized (Andrade et al, 2016;Hevener, 2018). In silico methods provide rapid and inexpensive techniques for quick lead test verification which proceed with in vitro cell testing.…”

Engineering in vitro models of hepatofibrogenesis

“…This is because animal models combine the native ECM microenvironment, different cell types, as well as oxygen and nutritional flows [95,96]. Limitations of using animal models are numerous; such as the non-human origin, significant differences in metabolic capacities, cytochrome P450 isoforms activity, interspecies physiologies, drug bioavailability and half-life, and disease adaptive mechanisms [97][98][99][100]. Many of these compounds fail due to undesirable toxicity and/or lack of clinical effectiveness, which is usually observed during the most expensive phase of clinical development i.e.…”

In vivo Studies for Drug Development via Oral Delivery: Challenges, Animal Models and Techniques

“…Usually, in vitro analyses are performed in the early stages of the drug discovery process, when the selectivity and possible interactions of the candidate drug towards the desired therapeutic target are established [14]. In vitro studies first focus on drug absorption, distribution, metabolism, and excretion which allows a more direct assessment of drug performance [15].…”

“…This is achieved through the study of drug dispersion, absorption/dissolution and permeability using samples of tissue, cell, or bacteria outside of their biological systems. Through these in vitro studies, the activity of the candidate drug upon different features, such as the induction of cell death and proliferation, changes in gene expression, changes in the protein profile, biochemical dosage of mediators, changes in cell cycle assessment, multidrug resistance potential, and others is observed [14]. Nowadays, in vitro pharmacological profiling including the absorption, distribution, metabolism, excretion and toxicity studies are is increasingly being used earlier in the drug discovery process to identify undesirable off-target activity profiles that could hinder or halt Clinical studies on humans 6…”