Population characteristics of biological systems influenced by multicomponent random and uniform variation.

The total variability associated with the pharmacokinetic disposition of seven therapeutic agents was decomposed into its source components. After differentiating and isolating random components from fixed uniform components of variance, the proportional contribution of random intersubject and intrasubject variance was evaluated. Statistical analysis utilized a mixed-effects probabilistic model which incorporated both random effects and fixed day-to-day effects. In some cases, time-within-day diurnal effects were also incorporated. While significant intersubject effects were found for all seven drugs studied, three of them were characterized by predominant intrasubject variance. Since intrasubject variance represents a measure of the stability of drug disposition, characterization of its relative magnitude is fundamentally important in assessing the therapeutic consequences of a given treatment at any given time. Significant diurnal effects were found which were strikingly invariant.