Toxicokinetics (TK) testing is an integral component of toxicological studies. Toxicological studies, including single-dose in-human studies and repeat dose toxicity studies, provide deeper insights about what the drug levels should be in subsequent phases of clinical trials.
But what is a TK study?
Toxicokinetics studies generate pharmacokinetic data for supporting nonclinical toxicity studies. It evaluates a drug compound during its course through a toxicity study in animal models. A toxicokinetic process describes a relationship between systemic drug exposure and the dose levels and duration of a toxicity study.
Toxicokinetic parameters are similar to the ADME properties of a drug compound. If appropriately utilized, ADME properties and TK analysis can better explain any negative results that may arise in toxicity analysis.
How do ADME properties influence toxicokinetic study data?
In both humans and animals, a drug product may undergo a series of changes as it passes through different compartments of the body. ADME stands for absorption, distribution, metabolism, and excretion. ADME can quantitatively modify a drug by altering concentration vs. time-dependent characteristics and qualitatively by having a toxic or therapeutic effect. Hence, understanding ADME implications can help sponsors better assess a potential drug compound.
Absorption relates to how a drug is absorbed in the body. How a drug is administered in the body dictates the rate of absorption and where a drug is absorbed in the body. Similarly, the drug formulation combined with the route of administration has a massive impact on the rate of dissolution, which may, in turn, affect the bioavailability of a drug compound. Thus deciding the best formulation and route of administration that closely relates to the intended end-use can help save a lot of time and resources.
Distribution relates to where a drug compound is distributed after it reaches the bloodstream. Concerning toxicokinetic analysis, distribution can be described as transferring drug molecules from the blood to body compartments or other body fluids. The volume of distribution is the ratio of the total drug present in the body to the drug concentration in blood plasma.
Metabolism is described as the change in the chemical composition of a drug once it travels through different body compartments. Several enzymes are responsible for the metabolism of a drug compound, and chemical changes should be critically considered as some drugs are still active after undergoing metabolism. Moreover, the presence of enzymes largely depends on the species, age, and sex. Hence, researchers should consider appropriate animal models with a similar response as humans for TK analysis.
Excretion is the process of eliminating the drug and its metabolites from the body. The rate at which a drug product is excreted is crucial in nonclinical toxicology studies as a rapid rate of excretion indicates improper drug distribution, and slow excretion can cause toxic effects in the body.
As toxicokinetic analysis establishes a relationship between systemic exposure and toxic effects, they form an integral component of the preclinical drug development process. Moreover, recent advancements in microsampling techniques are pushing boundaries and opening new avenues for toxicokinetic testing.