Pharmacokinetic analysis

On some occasions, the body does not behave as a single homogeneous compartment, and multicompartment pharmacokinetics are required to describe the time course of drug concentrations. In other instances certain pharmacokinetic processes may not obey first-order kinetics and saturable or nonlinear models may be required. Additionally, advanced pharmacokinetic analyses require the use of various computer programs, such as those listed on the website http //www.boomer.org/pkin/soft.html. 

Repeated dose chronic toxicity studies are performed on two species of animals a rodent and nonrodent. The aim is to evaluate the longer-term effects of the drug in animals. Plasma drug concentrations are measured and pharmacokinetics analyses are performed. Vital functions are studied for cardiovascular, respiratory, and nervous systems. Animals are retained at the end of the study to check toxicity recovery. Table 5.2 shows the duration of the animal studies, which depends on the duration of the intended human clinical trial. Appendix 6 summarizes the information to be submitted to regulatory authorities. 

In summary, because of the differences between assays, careful consideration of which assay has been applied is highly recommended when evaluating the concentration data of mAbs in pharmacokinetic analyses. 

Karlsson, M. O., Sheiner, L. B. The importance of modeling interoccasion variability in population pharmacokinetic analyses. 

Information provided in this chapter should make it easier for a researcher to choose a particular method and to have greater confidence in evaluating reported results of pharmacokinetic analyses. 

To facilitate the understanding of the pharmacokinetic concepts, the examples given previously are for the simplest and the most effective route of administration, that is, intravenous administration. When exposure is to toxic compounds (e.g., occupational or environmental exposure), however, other routes are frequently involved. These routes include respiratory, cutaneous, mucous, or oral uptake. In such cases, pharmacokinetic analyses are more complex since they should take into account the various processes responsible for the uptake of a xenobiotic. Usually, this consists of introducing into equations an additional term that contains a rate constant describing the uptake, operating in a direction opposite to, yet not conceptually different from the elimination rate constant. 

Many early PBPK modeling efforts were based on the Simusolv software, and support for this seems not readily available at the present time. More recently the ACSL and Berkeley Madonna (University of California, Berkley, CA) have become more widely used. In addition to these computer software packages, Haddad et al. [35] demonstrated the application of a spreadsheet program to support a PBPK model, and Trent University (Peterborough, Ontario, Canada, updated 2003) made available a spreadsheet program to run PBPK models. Further there are several computer-assisted applications, several as freeware, to perform pharmacokinetic analyses and interpret in vitro enzyme kinetic data (see Chapter 3). 

Krishnan, K., Clewell, H. J., Ill, and Andersen, M. E. (1994). Physiologically based pharmacokinetic analyses of simple mixtures. Environ Health Perspect 102(Suppl 9), 151-155. 

Population pharmacokinetic analyses are fraught with problems. This chapter was meant to explore these issues and present real-world problems and solutions to the reader. Some topics, like missing data, could not be covered in their entirety. Indeed, entire books have been written on some of the topics just briefly covered herein. Obviously the reader is referred to these texts for greater detail. With the topics presented in the last chapter on theory and this chapter on prac-... 

More intensive pharmacokinetics analyses have to be done to establish receptor-binding data. 

Assumptions and Assumption Testing Options for Population Pharmacokinetic Analyses... 

These examples illustrate the need to better estimate drug toxicities in humans to avoid lengthy phase I trials as well as severe drug toxicities. Toward this end, pharmacokinetic analyses are frequently being included in the toxicology protocols. Recently, drug microdosing have been proposed in humans to understand pharmacokinetic properties before projected doses are administered. This aspect is discussed further in Section 3.4.2. 

Li L, Shaik AA, Zhang J, et al. Preparation of penta-O-galloyl-3-d-glucose from tannic acid and plasma pharmacokinetic analyses by liquid—liquid extraction and reverse-phase HPLC. J Pharm Biomed Anal. 2011 54 545-550. 

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