What is the Scope and Significance of TK Study in Drug Development

In terms of the process involved, a TK study is very similar to PK study. The major difference is that toxicokinetics is often studied at supratherapeutic doses. In broad terms, toxicokinetics follows the general path of ADME (Absorption, Distribution, Metabolism, and Elimination) of a drug.

Each of the aforementioned factors can affect the toxicity of a drug. A tox study must, therefore, consider each of these and gather relevant data. A preclinical study can follow GLP guidelines or choose non-GLP guides. However, GLP toxicology studies FDA is necessary for NOAEL (No Observed Adverse Effects Level). This is done to ensure the robustness and accuracy of the data.

Greater emphasis is placed on NOAEL as it plays a major role in the recommended doses in a clinical trial. Robust TK data is necessary to translate animal data from preclinical studies to doses with relevance to humans.

Toxicokinetics and ADME

Planning a toxicokinetic program and finding a suitable TK assay starts from early development. Often, TK analysis is involved in drug discovery support and thus the program planning starts very early. In the ADME process, specific choices may lead to greater chances of toxicity. These are:

  • In Absorption, drugs that use active transport or absorbed through carrier-mediated mechanisms are less prone to toxicity. Drugs absorbed through passive distribution may carry a larger risk.
  • For Distribution, drugs with a large volume of distribution are more prone to toxicity than drugs with limited distribution ability.
  • During Metabolism, if enzymes with a high turnover metabolize the drug, it is likely to be less prone to toxicity.
  • In Elimination, pharmacologically inactive drug metabolites carry a lower risk.

While these represent a general scenario, as a tox study progresses, the results become clearer. The information so gathered can be used to guide the design, formulation, and route of administration of the drug.

Since blood supply is not the same for every tissue, TK studies often use alternative means to check distribution. The common choice in this scenario is using blood plasma, though other techniques may also be employed.

Deciding on Drug Dosage and Other Characteristics

Toxicokinetics provides valuable information related to drug use in humans. Translating the data from preclinical trials to human use can be a bit tricky. However, the use of toxicokinetics paves the way for understanding several important characteristics of the trial drug.

TK Study can help identify potential gender differences in the use of the drug. A drug may behave differently in male and female patients. With the backing of a tox study, the information can be available earlier. Similarly, it can help establish the maximum feasible dose, the possibility of accumulation, and the induction or inhibition of metabolism.

Toxicokinetics with Early Drug Development and Discovery

The use of TK assays in establishing the viability of the NCE (New Chemical Entity) is fairly common. High-throughput screening methods (HTS) are often used with TK assays to analyze thousands of chemicals in a day. This may also be paired with other methods and techniques like NMR and LC-MS/MS.

Conducting a preliminary tox study during drug discovery in biolab can save a significant monetary and time investment. While it aids in the discovery of the NCE, the use of toxicity in the early stages of development also provides the ground for the early establishment of a toxicokinetic program.

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