Pharmacokinetic-pharmacodynamic model Subject

Fig. 12.4 Pharmacokinetic-pharmacodynamic model ofthethrombopoietic effects of a thrombopoietin analogue (PEG-rHuMGDF) in healthy volunteers. The intrinsic longevity of platelets (A), nonlinear random destruction of platelets (p), and the intra-subject variability...

Salazar, D., Much, D., Nichola, P., Seibold, J., Shindler, D., and Slugg, P., A pharmacokinetic-pharmacodynamic model of d-sotalol Q-Tc prolongation during intravenous administration to healthy subjects, Journal of Clinical Pharmacology, Vol. 37, No. 9, 1997, pp. 799-809. 

Jiang, X., E.Y. Blair, and A.J. McLachlan. 2006. Investigation of the effects of herbal medicines on warfarin response in healthy subjects A population pharmacokinetic-pharmacodynamic modeling approach. /. Clin. Pharmacol. 46(11) 1370-1378. 

N. Minton, and W.K. Cheung. 2005. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects. Eur. J. Pharm. Sci. 26 295-306. 

In general, multiple (up to 30-40) blood samples can be obtained per subject to measure dmg and metabolite concentrations as well as biomarkers in these phase I clinical trials. Furthermore, pharmacodynamic measurements can be included to get a first impression on the drug effect in humans, however, limited by the fact that healthy volunteers were studied and not patients. As strict inclusion and exclusion criteria are used, the demographic characteristics of the healthy volunteers do not provide sufficient spread to investigate the effect of intrinsic factors. Therefore, phase I trials provide very rich data to develop pharmacokinetic and pharmacodynamic models on biomarker, but cannot be used to develop models for efficacy, safety, influence of patient factors on PK and/or PD and disease progression. 

A. N. Kong, E. Ludwig, R. L. Slaughter, P. M. Distefano, J. Demasi, J. E. Middleton, and W. J. Jusko, Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects. Clin Pharmacol Ther 46 616-628 (1989). 

S. Weller, K. M. Radomski, U. Lou, and D. S. Stein, Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 44(8) 2052-2060 (2000). 

Complex pharmacokinetic/pharmacodynamic (PK/PD) simulations are usually developed in a modular manner. Each component or subsystem of the overall simulation is developed one-by-one and then each component is linked to run in a continuous manner (see Figure 33.2). Simulation of clinical trials consists of a covariate model and input-output model coupled to a trial execution model (10). The covariate model defines patient-specific characteristics (e.g., age, weight, clearance, volume of distribution). The input-output model consists of all those elements that link the known inputs into the system (e.g., dose, dosing regimen, PK model, PK/PD model, covariate-PK/PD relationships, disease progression) to the outputs of the system (e.g., exposure, PD response, outcome, or survival). In a stochastic simulation, random error is introduced into the appropriate subsystems. For example, between-subject variability may be introduced among the PK parameters, like clearance. The outputs of the system are driven by the inputs... 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

Pharmacokinetics is closely related to pharmacodynamics, which is a recent development of great importance to the design of medicines. The former attempts to model and predict the amount of substance that can be expected at the target site at a certain time after administration. The latter studies the relationship between the amount delivered and the observable effect that follows. In some cases the observable effect can be related directly to the amount of drug delivered at the target site [2]. In many cases, however, this relationship is highly complex and requires extensive modeling and calculation. In this text we will mainly focus on the subject of pharmacokinetics which can be approached from two sides. The first approach is the classical one and is based on so-called compartmental models. It requires certain assumptions which will be explained later on. The second one is non-compartmental and avoids the assumptions of compartmental analysis. 

Pharmacokinetics, related when possible to the observed drug effects, is a powerful and critical component of the pivotal step from animal research to human research in the drug development process. Data for chosen compounds will commonly also have been subjected to simultaneous modeling of pharmacokinetic and pharmacodynamic data from animals, again in an effort to optimize the chances that the drugs chosen will have the proper-... 

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