Toxicology (TK) is the branch of pharmacology that describes the behavior and effects of drugs at supratherapeutic doses. At normal concentrations, drugs are absorbed and eliminated throughout the body based on their affinity for various enzymes, transporters, and receptors. At very high drug concentrations, those enzymes, transporters, and receptors become saturated, usually resulting in very different behavior and effects of the drug.
The tools used to perform toxicokinetic analysis are identical to those used to perform pharmacokinetic analysis. The only difference is that toxicokinetics involves toxic doses, whereas pharmacokinetics typically involves lower doses. Toxicokinetic analysis is used to determine the exposure levels at which toxic effects are observed. This is done to establish the No Observed Adverse Effect Level (NOAEL). The NOAEL is used to guide dosing recommendations for clinical testing.
Besides confirming exposure and establishing exposure parameters associated with the NOAEL, TK is necessary to identify potential gender differences, dose-limiting absorption and/or metabolism. This information may confirm suitability of the animal species used in the toxicity evaluations (relevance to humans), potential gender differences in humans, dose selection (maximum feasible dose), accumulation, and/or induction/inhibition of metabolism.
Factors that Affect Toxicity
There are many factors that determine a drug’s toxic potential. They include:
Mechanism of Absorption: Drugs absorbed by active transport or carrier-mediated mechanisms are typically prone to less toxicity than drugs absorbed by passive diffusion.
Distribution: Drugs with a large volume of distribution are more likely to be toxic than those that are limited in their ability to distribute throughout the body.
Efficiency of Biotransformation: Drugs metabolized by enzymes with a high turnover are less likely to have high levels of toxicity.
Nature of Metabolites: Drugs that are transformed into pharmacologically-inactive molecules are less likely to be toxic than drugs whose metabolites have physiological effects.
GLP and Non-GLP Tests
Toxicology studies are typically conducted in animals during pre-clinical testing. In order to use the results of a study to support marketing applications, the study must comply with Good Laboratory Practices (GLP). GLP consist of principles and standards that ensure the quality and integrity of scientific studies. If the study will not be used to support marketing applications, as may be the case for discovery, pilot, or screening studies, non-GLP tests are usually sufficient. This can save time and money during the development process. Our TK experts can help you decide whether a GLP or non-GLP study is appropriate for your toxicokinetics needs.
Our TK experience covers every route of administration, type of toxicity study, and expertise in complex nonclinical study designs. In addition, our clients have direct access to some of the most experienced TK scientists in the industry. Listed below are several of the services we offer:
- GLP and non-GLP TK analyses
- Study design including dose selection, frequency and sample collections
- Nonclinical protocol development
- GLP-compliant validated computing environment for conducting TK analyses
- Rapid and thorough Quality Assurance Unit (QAU)
- Onsite archiving of GLP study materials
- Robust report templates
Our clients have direct access to some of the most experienced TK scientists in the industry. Whether you need TK analyses, interpretation of your TK results, advice on next steps, or other TK services, our team will work with you to determine the most appropriate and cost-effective options for your drug development program.
Contact us to find out how our TK experts can help your product achieve regulatory milestones needed to reach the market.