NOVEL ANALYSIS OF NONLINEAR PHARMACOKINETIC SYSTEMS (VOLTERRA, COMPUTER MODEL KINETICS)

LUIS A SUAREZ, Purdue University

Abstract

In pharmacokinetics the processes of distribution, metabolism and excretion are frequently analyzed and quantified in terms of mathematical models. These processes are often assumed to be linear even though it is recognized that they are of a nonlinear nature. Previous approaches to the analysis of nonlinear pharmacokinetic systems have been based on specific nonlinear pharmacokinetic models typically involving classical linear compartmental principles incorporating nonlinear Michaelis-Menten elimination kinetics. It is advantageous to characterize nonlinear pharmacokinetic systems in a model independent fashion since model independent techniques are more generally applicable and do not have the drawback of the model dependent (structured) methods. The objective of this thesis is to develop an extension of the principles and methodology of the linear system approach to deal with nonlinear pharmacokinetic systems. The following methods were developed and tested: the Volterra power series approach, which has linear systems as a special case; the Autonomic approach, which has been successful in describing the pharmacokinetics of drugs with distribution phases which are Autonomic approach, which has been successful in describing the pharmacokinetics of drugs with distribution phases which are short relative to the elimination phase; and, the Nonautonomic approach which may be considered a generalization of linear and nonlinear drug disposition with a central elimination.

Degree

Ph.D.

Subject Area

Pharmaceuticals

COinS