17.13: Toxicokinetics: Overview

Studies that assess how a drug is absorbed, distributed, metabolized, and excreted (ADME) at toxic doses are termed toxicokinetics. Understanding toxicokinetics helps predict adverse drug reactions (ADRs) and manage toxicity in humans.

Toxicokinetics differs from pharmacokinetics mainly in the dose levels studied, with toxicokinetics focusing on higher toxic doses. The kinetics at these levels can be non-linear due to altered physiological processes. Toxicodynamics examines the relationship between drug concentration and its toxic effects.

Preclinical toxicokinetic data play a pivotal role in FDA approval and global drug regulation. It not only helps validate animal models, determine safe starting doses for human trials, and design dose regimens, but also provides crucial insights for clinicians to establish safety margins, pathologists to understand drug toxicity mechanisms, and reproductive and developmental toxicologists to select appropriate doses in teratology studies. The toxicokinetic data are instrumental in ensuring drug safety and efficacy.

Ultimately, TK/TD studies translate animal toxicity data to human contexts. This crucial step guides drug safety throughout development and post-marketing, ensuring that the drugs we develop are not only effective but also safe for human use.

Toxicokinetics, abbreviated as TK, studies how a drug is absorbed, distributed, metabolized, and excreted at higher doses, which may lead to toxicity.

While toxicokinetics and pharmacokinetics share principles and models, they focus on different dose ranges—namely, the toxic and therapeutic ranges, respectively.

Toxicokinetics studies high, toxic doses that may affect drug solubility in the intestines, leading to precipitation. Additionally, saturated processes, such as enzymatic metabolism and protein binding, lead to nonlinear kinetics at toxic doses, unlike the typically linear kinetics observed at therapeutic doses.

Toxicodynamics or TD explores the relationship between toxic drug doses and the resulting adverse effects.

Preclinical TK/TD studies correlate animal toxicity data with human safety by estimating the human equivalent and the maximum recommended starting doses. They also validate animal models, aid in dose selection for human trials, assist in designing safe pharmacokinetic studies, and identify target organs for toxicity.