Prior to any drug getting to market for human consumption there is a long and complex journey of discovery, development and rigorous evaluation. Most potential drugs fail along the way with only about 12% of the drugs that entered clinical trials reaching the pharmacy shelves.

 
Toxicology research laboratories play a crucial role in this drug discovery journey. By contributing to the understanding of the safety and efficacy of potential drug candidates, they help to ensure that only the most promising compounds progress through the drug development pipeline.

Toxicology testing can be conducted in vitro, in vivo and in silico in a series of testing methods that are essential in guiding researchers and regulators towards the development of safe and effective treatments – sometimes called the move from bench to bedside. 

In this article we delve into the various stages of toxicology testing during the drug discovery lifecycle. 

Where does preclinical research appear in the drug lifecycle?

Deciding whether a drug is ready for clinical trials in humans involves extensive preclinical studies to gather preliminary efficacy, toxicity, pharmacokinetic and safety information. Samples of the drug candidate are tested using in vitro (test tube or cell culture) and in vivo (animal) experiments. It is also possible to perform in silico profiling using computer models of the drug–target interactions.

The aim of pre-clinical trials is to extensively test, improve and refine a drug candidate until enough evidence is gathered to proceed safely with clinical trials. It is a crucial series of studies which evaluate whether an intended treatment can reach regulatory safety thresholds prior to clinical trials in humans.

Preclinical toxicology testing is carried out by researchers in laboratories that are accredited and inspected by government regulators such as the MHRA in the UK and the FDA in the US, and that are compliant with internationally-accepted standards such as GMP (Good Manufacturing Practice) and GLP (Good Laboratory Practice). For more details on GMP and GLP see our previous blogs here and here.

 
In Vivo Toxicology Studies 

In vivo testing refers to experiments conducted in living organisms, typically animals. These tests evaluate the safety and efficacy of drug candidates in a living system. In vivo testing is often considered the gold standard for toxicology assessments because it can replicate the complex interactions between the drug and the organism. However, it also raises ethical concerns regarding the use of animals in research.

Toxicology testing laboratories that conduct experiments using animals have a responsibility to ensure the highest standards of animal welfare, as well as adhere to the legal requirements that toxicology testing must be justified to the regulator and be carried out only where alternative methods for testing a substance do not exist.  At Hoeford we have also implemented the 3Rs framework, meaning we are committed to the Reduction, Refinement and Replacement of in vivo animal testing.

The safety and efficacy assessments that in vivo toxicology studies provide include: 

Early Safety Assessment:
To assess the safety and toxicity profile of potential compounds during the early drug development stage, these tests provide valuable insights into the compound's pharmacokinetics, bioavailability, and potential for adverse effects. This information helps toxicology researchers to determine appropriate dosage ranges and identify any potential toxic effects.

Determining Dose-Response Relationships:
Further toxicity testing allows for the establishment of dose-response relationships, which helps researchers to identify the optimal dosage and determine the maximum tolerated dose (MTD) - the largest quantity of the compound which can be inhaled, digested or consumed without causing significant adverse effects. This is crucial data for subsequent stages of drug development, including formulation optimisation and clinical trials.

Investigating Organ-Specific Toxicity:
In vivo toxicity studies also enable the evaluation of organ-specific toxicity and potential systemic effects of drug candidates. By examining specific target organs or systems, including the liver, kidneys, cardiovascular system, or central nervous system, researchers can identify any adverse effects that may arise and assess the compound's overall safety profile.

Assessing Carcinogenicity and Mutagenicity:
In vivo testing also plays a pivotal role in determining the carcinogenic and mutagenic potential of drug candidates. These long-term studies involve prolonged exposure to compounds to help identify potential risks associated with cancer development or genetic mutations while assessing overall safety and potential for long-term use.

In Vitro Toxicology Testing

In vitro toxicology testing refers to experiments conducted outside the living organism, typically using cell cultures or tissue samples to assess the potential toxicity of drug candidates and evaluate the effects on cellular viability, function, and other relevant endpoints. Compared to in vivo testing this is less costly and more time-efficient and is often used at the early stages of drug discovery to identify and prioritize drug candidates for in vivo studies.

The early screening and mechanistic insights of in vitro testing include:

Early Compound Screening:
High-throughput screening (HTS) is an automated testing system that allows rapid evaluation of a large number of compounds in early stage drug discovery to identify potential lead compounds with desired properties. Screening these potential compounds for their toxic effects serves as an initial filter, enabling researchers to prioritise drug candidates with the most favourable safety profiles for further testing.

Predictive Modelling and Quantitative Structure-Activity Relationships (QSARs):
The development of predictive QSAR models based on data obtained from in vitro tests further enhances the screening and prioritisation of compounds. These models help researchers to predict toxicity outcomes and facilitate accurate decision-making during drug development.

Cytotoxicity, metabolism and pharmacokinetic testing:
These types of in vitro toxicology studies provide assessment of cell exposure to a substance, Cytotoxicity testing uses cell cultures to evaluate the potential of a substance to cause damage to cells, while metabolism and pharmacokinetic studies evaluate the absorption, distribution, metabolism, and excretion (ADME) of a substance in the body using tissue samples. 

In Silico Toxicology Testing

In silico toxicology is considered one of the alternatives to animal testing and refers to the use of computer modelling and simulation techniques to predict the toxicological outcomes of drug candidates. Computational models are developed based on available data and knowledge of the compound's structure and properties. These models can help identify potential toxic effects and prioritise compounds for further evaluation. 

In vivo, in vitro and in silico testing methods are used at different stages of the drug discovery process. In vivo testing provides a comprehensive evaluation of the interaction between a drug and a living organism. In vitro testing offers cost-effective and fast assessments in the early stages of drug discovery. In silico toxicology testing utilizes a variety of computational tools for gathering, analysing, modelling, simulating, and predicting the potential toxicity or toxicokinetic properties of a substance before conducting, or in the absence of, any experimental study, be it in vitro or in vivo. 

These different types of toxicology studies complement each other and together provide a comprehensive understanding of the safety and potential risks associated with drug candidates. They help researchers make informed decisions about the progression of drug candidates through the development pipeline and contribute to the overall success of drug discovery efforts.

As a toxicology research laboratory we are passionate about the continuous advancement of toxicology testing methodologies and how they are shaping the future of drug discovery to enhance patient safety and improve global healthcare outcomes. 

Partner with Hoeford Research for in vivo toxicology results you can trust. Contact us to start your drug discovery journey today!