- March 9, 2023
In innovative drug development, conducting toxicology studies to determine the type, dose, and mechanism of toxic response to a drug is essential to deciding on a drug’s safety and efficacy, developing safe drug use strategies, and avoiding unnecessary drug toxicities.
Generally, drug toxicology research includes the following :
- Toxicity testing: drug toxicity tests are conducted in experimental animals or cells to assess the harmful effects of drugs on organisms.
- Mechanism of toxicity studies: To understand the causes of toxic reactions by studying the mechanism of action of drugs.
- Toxicity assessment: To assess drug safety and potential risks and develop reasonable drug use strategies.
- Toxicological monitoring: to monitor the population using the drug and understand the long-term toxicity and adverse effects.
In the early stage of R&D, the early combination of toxicological screening and evaluation can help improve the success rate of innovative drug development and accelerate the R&D process.
Three main early drug toxicity evaluation methods exist: virtual, in vitro, and in vivo. Let’s take stock of several common drug early toxicity screening strategies today.
1. Computer-aided prediction model
Computer-aided prediction models are qualitative or quantitative predictions based on molecular structure information of compounds and help in the preferential selection of lead compounds.
In cardiac myocytes, the hERG potassium channel affects the repolarization process of the cardiac action potential. In recent years, several drugs have been withdrawn from the market because blocking this channel causes prolongation of the QT interval.
Using computer-aided drug design (CADD) to predict the potential hERG toxicity of drugs and guide drug design and modification is convenient, fast, and inexpensive. Researchers have developed many models and tools to predict hERG toxicity.
Quantitative structure-activity relationship (QSAR) modeling is an efficient and straightforward computer simulation method for predicting the potentially toxic effects of other compounds with known structures on the body by modeling a group of compounds’ structure and harmful effect data.
2. In vitro high-throughput screening models
1. Genetic toxicity
Genotoxicity evaluation is a key part of drug safety evaluation research, not only is it one of the important indicators for early toxicity screening of lead compounds, but also an important evaluation method and technique in standardized preclinical drug safety evaluation research, which is an important basis for judging whether a new drug can enter clinical trials.
For example, the bacterial revertant mutation test (Ames) can sensitively detect mutations caused by DNA damage and occupies an important position in the early stage of new drug development.
2. Cardiotoxicity
The prolongation of OT intervals, which causes tachycardia of the tip-twist type and lethal arrhythmias, is an important issue that must be considered during the development of innovative drugs.
IKr plays a critical role in the overall action potential time course. National drug regulatory authorities require new chemical entities to undergo a comprehensive hERG activity and QT interval evaluation following International Conference on Harmonization (ICH) guidelines.
Establishing a cardiotoxicity evaluation system for hERG potassium channels is essential to save time and cost in developing new drugs. The diaphragm clamp technique is the most commonly used method to detect the hERG cardiotoxicity of drugs.
3. Nephrotoxicity
The kidney is the most common target organ of drug toxicity, and the traditional kidney function test method mainly relies on biochemical blood indexes. The abnormal increase of these indexes often indicates that the kidney function has been moderately damaged or above.
Predicting the nephrotoxicity of drugs is an essential part of drug safety evaluation. Establishing an in vitro nephrotoxicity optimization screening model is necessary to reduce the cost of drug development and accelerate the research and development process.
4. Hepatotoxicity
Hepatic transporter proteins play an important role in bile formation and drug disposition. Drug-transporter protein interactions are associated with hepatotoxicity; therefore, hepatotoxicity plays a vital role in drug metabolism and clearance and needs to be evaluated in preclinical studies of new drugs.
The in vitro culture model of hepatocytes is widely used for in vitro hepatotoxicity screening. In addition, in vitro models constructed using organ-on-a-chip technology offer some significant advantages for assessing the drug-induced liver injury.
3. In vivo screening models
Pharmacologists and toxicologists favor the model organism zebrafish due to advantages such as a wide range of toxicological endpoints, a small number of samples used, a short test cycle, and the similarity of tissue structure to mammals.
Zebrafish are used to identify the potential toxicity and safety of various drugs and chemicals to various organs, and as an organic holistic life form, they can serve as an effective link between in vitro cell or tissue culture models and in vivo mammalian models.
Zebrafish models have been shown to have potential applications in predicting general toxicity (acute toxicity, developmental toxicity) and target organ toxicity (liver, heart, ototoxicity, etc.) as well.
Toxicity is a significant cause of failure in late-stage drug development. Early toxicity evaluation of compounds can significantly improve the success rate of drug development and reduce the occurrence of toxic side effects. Bringing safety evaluation to the early stage of drug development can help shorten the drug development cycle and reduce development costs.
Medicilon boasts professional teams and practical experience in drug safety evaluation and can promise high-quality data and fast turnaround time to support various drug safety evaluations. Our toxicology research uses different animals, from dose design and experimental research to histological and pathological study (including clinical detection). The analysis can be carried out according to non-GLP or GLP standards.
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