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, 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 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 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.
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.