What is toxicology?

Toxicology also called the science of poisons, is a branch of science, medicine, and biology that studies adverse effects that occur in living organisms and the environment due to chemicals, substances (including environmental agents and chemical compounds found in nature, as well as pharmaceutical compounds that are synthesized for medical use by humans. These substances may produce toxic effects in living organisms, which can include, but are not limited to, disturbances in growth patterns, discomfort, disease, and even death), and situations. The job of scientists and researchers working in this sphere is to find patterns by which substances exert toxicity, detect the presence of these substances in various sample types, and treat biological organisms that have been exposed to certain toxicants. 

In order for pharmaceutical items to be developed and approved, toxicology studies are critical. Two species are required for toxicological testing by the FDA and other government bodies (a rodent and a non-rodent). Good Laboratory Practice for Nonclinical Laboratory Studies is mandated by the 21 CFR Part 58, and these studies are carried out to ensure proper handling of test subjects and scientific reliability. When given at a high enough dose, most novel chemicals will produce toxic side effects or adverse events. It is important to conduct preclinical toxicity and toxic kinetic studies to determine if the drug is safe for human testing and to define the therapeutic and toxic limits. It is important for clinicians to be aware of adverse events that may occur during preclinical testing. It is important for doctors to be aware of the toxic effects on target organs so that they can reduce or stop treatment if necessary. As a result of these investigations, toxicology and toxic kinetics (TK) can be used to understand better a drug’s adverse effects on the human body and specific target organs. Different TK doses are examined in this study to find out how they alter the body’s exposure to the drug. In order to determine linearity with respect to exposure linearity with respect to dose, metabolic saturation, chemical accumulation, and related possible side effects and the systemic exposures where they occur, TK studies help researchers determine linearity. 

What are IND-enabling studies?

IND-enabling studies include in vitro (“in glass” such as a test tube or petri dish, used to describe work that is performed outside of a living organism. For example, in vitro tumor models provide low-cost platforms for a pharmaceutical company to study the biological effects of the experimental drug candidates against cancer cells. The results of these studies can inform about the molecular mechanisms of each drug candidate and how these mechanisms may influence cancerous cells under defined conditions.) and in vivo (refers to researches that are done within entire living organisms such as animals, plants, or whole cells. For example, clinical trials focused on assessing the safety and efficacy of an experimental drug in humans are considered in vivo studies.) assessments that help to define the pharmacological and toxicological properties of the drug. This includes dose and exposure dependencies and the reversibility of toxic effects. The goal of the IND application is to show that with both safety and pharmacokinetic data, the drug candidate is safe for clinical studies.

Why are IND programs required?

The IND (Investigational New Drug) program application is required by the United States FDA (Food and Drug Administration) before any clinical (using humans) studies may be considered. For new drugs and even for most follow-on products, the results of certain IND-enabling studies must be submitted with the IND application to support the investigational drug use in humans.

 IND- enabling studies, at a minimum, shall provide the drug developers with the information on: 

• Pharmacokinetics (PK) that allows defining the metabolic pathway through absorption, distribution, metabolism, and excretion (ADME); plus recently required radiolabeled mass balance studies; 
• Pharmacodynamics and safety pharmacology; 
• Toxicology studies to evaluate the safety of a new drug candidate, and include single-dose toxicity and repeat-dose toxicity studies, adverse effects on the reproductive system and developing embryo or fetus, as well as assessment of mutagenic ability. 

The amount and variety of studies, that are reasonably necessary to support IND filings depend on the drug investigated, route of administration, patient population, drug indication, and other factors.  

Additional studies that allow assessing the risks associated with the use of the drug can be immunotoxicity and local tolerance testing. For pediatric patients, juvenile animal studies must also be conducted before clinical trials. 

Although IND-enabling studies are conducted in cell culture and on animal models, it takes from one to six years to decide whether the new drug has the potential for clinical trials. However, this is not the end of preclinical research. Additional studies, often long-term, are required to characterize the ability for long-term toxicity and carcinogenicity. 

It is also important to keep in mind Potential Chemistry, Manufacturing, and Controls (CMC) complications throughout IND-enabling studies. When a chemical composition is thoroughly identified and characterized it is more possible to get an accurate result.