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Toxicokinetics (TK) Study: Non-GLP or GLP testing for Compound Toxicity

Toxicokinetics is merely a pharmacokinetic study of the drug when administered at quantities much higher than the therapeutic dose to evaluate potentially toxic levels of the drug. Toxicokinetics is thus the appropriate term for the study of the kinetics of all substances at exposure levels ranging from therapy to toxicity. During a GLP toxicology study by FDA standards, the body reaches the maximum tolerated dose (MTD), the dose level yielding exposure of the drug to the point of toxicity. Understanding the dosage and systemic exposure of the drug during the toxicokinetic study is essential as this aspect defines the difference in a drug being therapeutic vs. toxic. This difference gives an understanding of the drug’s therapeutic index, representative of the safety margins between therapy (minimum efficacious dose) and toxicity (maximum tolerated dose or maximum feasible dose). The same drug given in a small dose may start healing at the site of action. But, when administered at a high dose, it can even be fatal for the human body.

The reason behind the necessity of Toxicokinetics lies in the study’s ability to provide insights on molecules’ systemic exposure related to adverse effects. This aspect is an especially important consideration for the cardiovascular system, the central nervous system, and respiratory assessments. Furthermore, single-dose studies carried under this analysis assist in predicting the duration and rate of exposure at the time of one dosing interval and whether systemic accumulation occurs following multiple administrations of the drug. This benchmark information provides the right dose levels for later stages of the compound development. Overall, the data obtained from a toxicokinetic study assesses the toxic responses of various drug compounds. The result of this study becomes the basis for knowing the right dose of a new drug safe for the human body. Moreover, the study may provide insights into how certain medications can diversely affect people of different ages, genders, and ethnicities.

Toxicokinetics (TK) Study: Absorption, Distribution, Metabolism, and Elimination

Toxicokinetics is essentially the study that helps in understanding how a substance enters the body and what happens to it inside the body. The term “disposition” is often used in the place of Toxicokinetics to describe how the body disposes of the drug over time.

Many factors impact Toxicokinetics, but here are the four most prominent underlying processes, namely absorption, distribution, metabolism, and elimination, in a TK analysis similar to PK analysis. These stages or processes assist in understanding how the body absorbs, metabolizes, and eliminates the administered drugs and can be correlated to toxicological assessments of exposure margins for safe clinical administration.

Absorption

Absorption, the first step of a toxicokinetic study, is the process of a substance entering the blood circulation. Whenever a toxin is administered to the body, it crosses a membrane to enter the systemic circulation in a process known as absorption. These toxins are absorbed into the body through various channels such as intestine, lungs, skin, etc. Every toxin is absorbed in the human body differently. While some are difficult or hardly get absorbed, others enter readily. Generally, the form of a toxin directly affects the ease of it being absorbed in the human body. For example, a toxin in gas form may be easily absorbed through lungs within minutes, while when prepared for oral consumption may take hours.

Distribution

Distribution describes the reversible transfer of drug within the body from one location to another. The distribution of a drug is affected by multiple factors including lipid-solubility, concentration in plasma and various tissues, and binding to plasma proteins, transport proteins, and tissues.

Metabolism

Metabolism is an irreversible process by which a drug is converted to other chemical entity (metabolite). Metabolism happens primarily in the liver. At the time of metabolism, the xenobiotic chemicals administered by the body are altered with the help of non-enzymatic or enzymatic reactions. The aim is the conversion of lipophilic compounds, which are poorly excreted, to the entities that can quickly be discharged from the body. If metabolism fails to convert these compounds, toxic reactions may follow.

Elimination

The drug chemicals are excreted from the system either as water-soluble metabolites or in their unchanged form. While the kidney plays an essential role in excreting water-soluble toxins from the body, excretion of other compounds needs the help of the biliary system, liver, etc.

NorthEast BioLab TK Assay and TK Analysis Services

We offer a wide range of TK Assays during the early discovery phase when a potential drug (NCE) is evaluated for ADME properties. Once an NCE is found suitable for further development, we also provide IND enabling Tox studies in animals. TK Assays in animals are critical for advancing drugs into the clinical phase. Toxicokinetic studies are run in various animal species depending on the therapeutic area and the most appropriate animal model. In general, toxicokinetic studies are conducted in at least two animal species. We develop fully validated bioanalytical methods for GLP toxicology studies in various biological matrices of all animal species.

After finishing your sample bioanalysis, NorthEast BioLab can complete your TK study by calculating relevant pharmacokinetic parameters for your compound. We’re happy to aid you in study and protocol design, study execution, interpretation of TK results, or guidance plus modeling of initial clinical doses for safety and efficacy testing. We maintain fully validated Phoenix WinNonlin software for non-compartmental analyses (NCA) and PK/TK modeling. Our team can provide informal/formal and audited reports for your study in any phase, from early discovery to clinical development.

The Basics of Bioanalysis

Bioanalysis is an essential tool in drug discovery and development for determining the concentration of drugs and their metabolites as well as various pharmacodynamics biomarkers in biological fluids. In these analyses, scientists use developed an….

Streamlined Toxicokinetics (TK) Studies to Advance your Therapeutics Program

We, at NorthEast BioLab, would assist with your challenging toxicokinetic studies. Since the TK analysis is a vital component of drug development, expert guidance during the end-to-end process is imperative. Knowing the toxicity of a drug compound along with its systemic exposure helps the scientists decide the correct drug dosage to be used in early clinical trials and development. Hence, carrying out the GLP toxicology studies utilizing a fully validated and reliable bioanalytical method is necessary.

While the TK study may be a lot like PK analysis, the difference in multiple aspects and evaluation is considerably high. As TK analysis helps mitigate or uncover the risks associated with a drug compound, we would ensure that the absolute integrity of your data and processes is maintained in full compliance with the global regulatory agencies.