PK/PD studies for toxicology

Pharmacology is the study of medication interactions with the human body with the interconnection of two major categories: pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetics (PK) is the study and description of drug activity in the body throughout time, including the mechanisms by which medications are absorbed, transported throughout the body, localized in tissues, and eliminated whereas the link between plasma and tissue drug and/or metabolite concentrations, time, and treatment response is defined as pharmacodynamics.

Pharmacokinetics and pharmacodynamics, which both play essential roles in evaluating a medicine’s safety and efficacy, quantify and explain the intricate biochemical interactions between the body’s natural processes and the chemical composition of a pharmaceutical drug.

Toxicology is a scientific subject that overlaps with pharmacology and encompasses the study of the harmful effects of chemical compounds on living organisms as well as the practice of detecting and treating toxins and toxicants. Toxicokinetics and toxicodynamics are concerned with the application of PK/PD concepts to the disposition of toxicants and their metabolites, as well as the time course of toxic or unpleasant events in the body.

Typical early drug development techniques include the manufacture and testing of multiple test articles with the objective of attaining disease target interaction with specificity, selectivity, and potency. PK/PD drug testing is done during early drug discovery in nonclinical efficacy species (usually mice) to establish whether a prospective medication has the appropriate exposure to achieve effectiveness following in vivo treatment. These early PK/PD studies are used to demonstrate the test article’s target specificity, sufficient systemic exposure to reach the therapeutic target to achieve efficacy and the interpreted biochemical mechanism of action in relation to the observed exposure and efficacy.

In a chemical screening cascade, related in vitro ADME analyses are frequently relevant. In vitro investigations may be done prior to in vivo dosing to estimate metabolic stability, cell permeability potential, protein binding, and drug interaction potentials. These tests may be used to screen out compounds that have unfavorable metabolic liabilities, poor absorption or inability to reach the therapeutic target, or a high potential for metabolic interactions with other medications or xenobiotics in the body.

A small number of preclinical (non-clinical) candidate molecules are further characterized at the conclusion of lead compound optimization and identification in preparation for preclinical toxicology and development. For batch scale-up, synthetic chemistry procedures may alter, and improvements or changes in compound purity and crystallinity may impact PK exposures in animals. In these circumstances, PK with scaled-up batches should be investigated for any variations from previous batches, and additional species are frequently tested to better understand single-dose PK/PD in efficacy model species and intended species for preclinical toxicity and toxicokinetics/toxicodynamics evaluations. PK/PD may be examined using different formulations, and other interactions and effects, such as fed vs. fasted states or gender differences.

Drug accumulation and steady-state evaluations are frequently performed by comparing PK/PD after numerous doses versus after a single dosage. Higher dosages can be evaluated to determine the maximum tolerated dose and the therapeutic index, which is determined as the ratio of the most endured dose to the least active dose. If multiple animal strains are employed for effectiveness testing, their results can be compared. To further understand compound PK/PD connections, data can be analyzed with efficacy model outcomes. ADME investigations in late discovery help with toxicology planning by predicting possible metabolic liabilities, changes in cross-species metabolism, and drug-drug interactions.

For preclinical toxicological research (nonclinical pharm/tox studies), the US FDA and other national regulatory agencies need a least of two species, including one rodent (rat, guinea pig) and one non-rodent (dog, monkey, minipig) to assess acute, sub-chronic and chronic toxicity at the proposed site of exposure. Toxicology investigations, in the great majority of situations, incorporate assessments of compound toxicokinetics/toxicodynamics to help in the interpretation of any reported toxicological consequences. Toxicology doses are often greater than those employed in previous PK/PD evaluations and effectiveness studies, ranging from the minimal effective dosage to the maximum tolerable dose. All elements of toxicological and toxicokinetic evaluations in these investigations are governed and carried out in accordance with 21 CFR part 58.