Pharmacokinetic principles animal studies

The present volume of the series Methods and Principles in Medicinal Chemistry focuses on the impact of pharmacokinetics and metabolism in Drug Design. Pharmacokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their pharmacologic, therapeutic, or toxic response in animals and man. 

The standardized guidelines have been compiled to cover test methods in animal studies and in vitro studies on absorption, distribution, metabolism cind excretion in the Notification No. 496 of the PAB in 1998. The guidelines can be applicable for the drugs to be submitted after October 1999. The following principles should be considered in order to select the most appropriate methods bcised on the characteristics of test substance. It is required that the exposure data related to toxicological studies be obtained before the first human study and other pharmacokinetic data before the completion of Phcise I study in principle in accordance with the guidelines on nonclinical safety studies for conducting clinical trials (Notification No. 1019 of the PAB, 1998). 

Interspecies scaling based on physiological modehng or, more commonly, allom-etry, has been used to predict pharmacokinetics in humans from animal pharmacokinetic data. " This has been applied to choosing doses for acute dose tolerance studies, since dose selection can then be based on pharmacokinetic principles. However, this approach has recently been criticized as less predictive than usually envisioned and providing estimates of human pharmacokinetic parameters that are so imprecise that its prospective use to choose doses for first-in-human dose tolerance studies is not warranted. ... 

Questions about the rapidity, extent, and duration of internal exposure to foreign chemicals are the province of the twin disciplines of pharmacokinetics and toxicokinetics. Pharmacokinetics is the study of foreign chemicals that act as therapeutic drugs. Their uptake, distribution, and elimination have been studied in detail in human subjects. Toxicokinetics is based on exactly the same principles as pharmacokinetics, but it is concerned with foreign chemicals with toxic, not therapeutic, effects. For obvious ethical reasons, toxicokinetic studies are limited to experimental animals. However, when dealing with the toxic ( side ) effects of therapeutic drugs, the line between pharmacokinetics and toxicokinetics becomes blurred and effectively disappears. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Allometric principles may be used to answer a variety of questions relevant to the application of pre-clinical pharmacokinetic data to the design of dose regimens for humans. Two examples are the use of data from animals to estimate the human pharmacokinetic parameters needed for selecting a starting dose for Phase I studies and the design of intraperitoneal dose regimens for antineoplastic drugs. 

---