Physiological pharmacokinetic modelling.

Abstract

1. The different types of models are described, with emphasis on the clearance-based one-compartment model, and on full physiological models which distinguish between a number of anatomical compartments interconnected through the body fluid system. 2. The clearance-based, one-compartment model incorporates physiological concepts, such as apparent volume of distribution, systemic availability, hepatic and renal clearance. As opposed to the classical rate constant-based model, it allows a study of the influence of plasma protein binding, hepatic intrinsic clearance and blood flow. The advantages of such an approach are illustrated in two typical situations, namely renal insufficiency and saturable protein binding. 3. In full physiological models each compartment represents a particular organ or tissue, further divided into vascular, interstitial and cellular spaces. Mass balance equations are written for each of these subcompartments. Shortcomings of such comprehensive models include difficulty in collecting tissue data, especially human, and sophisticated numerical techniques needed for parameter estimation. The main advantages are specific organ metabolism and transport, and the possibility of scaling up from animal to human. 4. The pharmacokinetic parameters important for new drug registration are also listed.