Mean time parameters in pharmacokinetics. Definition, computation and clinical implications (Part I)

Abstract

A mean time parameter in pharmacokinetics defines the average time taken for 1 or more kinetic events to occur. Due to the complexity of the subject, a great number of different mean time parameters may be defined. Three of these parameters which appear to be of greatest interest are discussed: mean residence time (MRT), mean transit time (MTT) and mean arrival time (MAT). Formal definitions for these parameters are presented and various methods of evaluating them are described. The concepts of kinetic spaces, of importance in dealing with mean time parameters, are broadly defined. The discussion of the theory behind mean time parameters begins generally with fundamental core relationships, valid for both stochastic and non-stochastic systems, and successively introduces increasing degrees of kinetic specificity, ending with a discussion of mean time parameters of specific pharmacokinetic models. The limitations and assumptions involved in the use of mean time parameters in the various models are highlighted, with examples to clarify the concepts discussed. Area under the moment curve/area under the concentration-time curve (AUMC/AUC), commonly used as a definition for the MRT of drug molecules in the body, should not serve as a definition but should instead be considered as a method of evaluating this parameter. The literature on mean time parameters as they relate to absorption, distribution, elimination, metabolites, dosing times and drug accumulation is discussed. The clinical implications of mean time parameters are also considered, particularly in relation to the prediction, evaluation and interpretation of pharmacokinetic data.