Development of pharmacokinetic models

Comparative Toxicokinetics. Qualitatively, absorption, distribution, metabolism, and excretion appear to be similar in humans and laboratory animals. However, quantitative variations in the absorption, distribution, metabolism, and excretion of benzene have been observed with respect to exposure routes, sex, nutritional status, and species. Further studies that focus on these differences and their implications for human health would be useful. Additionally, in vitro studies using human tissue and further research into PBPK modeling in animals would contribute significantly to the understanding of the kinetics of benzene and would aid in the development of pharmacokinetic models of exposure in humans. These topics are being addressed in ongoing studies (see Section 2.10.3). 

Thus total clearance can be estimated by independently predicting each of the major clearance processes indicated. The liver is by far the main route of clearance for most drugs, therefore it has been the focus for much of the development of pharmacokinetic modeling methods. 

Refinement and expansion of these steady-state mass balance approaches has led to the development of dynamic models which allow for estimation of the fraction absorbed as a function of time and can therefore be used to predict the rate of dmg absorption [37], These compartmental absorption and transit models (CAT) models have subsequently been used to predict pharmacokinetic profiles of drugs on the basis of in vitro dissolution and permeability characteristics and drug transit times in the intestine [38],... 

Absorption, Distribution, Metabolism, and Excretion. Levels of cresols in blood were obtained from a single case report of a dermally exposed human (Green 1975). Data on the toxicokinetics of cresols in animals were contained in two acute oral studies that provided only limited quantitative information on the absorption, metabolism, and excretion of cresols (Bray et al. 1950 Williams 1938). A more complete oral toxicokinetics study, in addition to studies using dermal and inhalation exposure, would provide data that could be used to develop predictive pharmacokinetic models for cresols. Inclusion of several dose levels and exposure durations in these studies would provide a more complete picture of the toxicokinetics of cresols and allow a more accurate route by route comparison, because it would allow detection of saturation effects. Studies of the tissue distribution of cresols in the body might help identify possible target organs. 

The committee recommends that efforts be made to develop human pharmacokinetic models early in the study-design process to understand the influence of such factors as metabolism, sampling time, and population variability, that are critical to interpretation of the biomonitoring data. 

During the first decades of the development of pharmacokinetic science, a lag time in pharmacological response after intravenous administration was often treated by applying a compartmental approach. If the plasma concentration declined in a biexponential manner, the observed pharmacodynamic effect was fitted to plasma or tissue compartment concentrations. Due to the lag time of effects, a successful fit was sometimes obtained between effect and tissue drug level [414]. However, there is no a priori reason to assume that the time course of a drug concentration at the effect site must be related to the kinetics in tissues that mainly cause the multiexponential behavior of the plasma time-concentration course. A lag time between drug levels and dynamic effects can also occur for drugs described by a one-compartment model. 

The development of a successful pharmacokinetic model allows one to summarize large amounts of data into a few values that describe the whole data set. The general procedure used to develop a pharmacokinetic model is outlined in Table 10.1. Certain aspects of this procedure have been described previously in Chapters 3 and 8. For example, the technique of curve peeling" frequently is used to indicate the number of compartments that are included in a compartmental model. In any event, the eventual outcome should be a model that can be used to interpolate or extrapolate to other conditions. 

The final area of computational toxicology to be discussed in this chapter applied to dermal absorption is the general area of pharmacokinetic models (see also Chapter 3). These are usually developed as extensions of whole animal-based models using classic compartmental [19,31] or physiological-based [32] approaches. These texts should be consulted for an overview of the... 

Obviously, one of the key tasks of a pharmacometrics service is the development of pharmacokinetic and pharmacodynamic models that serve as a mathematical representation of physiologic or pharmacologic phenomena. This is also one of the main activities that create a mockery of cost and schedule estimates. The complexity and scope of a pharmacometric model are limited only by the imagination, literature access, and computer resources of the pharmacometrician. Consequently, an effective model development process is one in which the extent of achievable... 

The focus of this book is primarily on the development of pharmacokinetic and pharmacokinetic-pharmacodynamic models. Models that are reported in the literature are not picked out of thin air. Useful models take time and effort and what is rarely shown is the process that went into developing that model. The purpose of this chapter is to discuss model development, to explain the process, and to introduce concepts that will be used throughout this book. Those criteria used to select a model extend to whether the model is a linear... 

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