Emergence of power laws in the pharmacokinetics of paclitaxel due to competing saturable processes.

Abstract

PURPOSE: This study presents the results of power law analysis applied to the pharmacokinetics of paclitaxel. Emphasis is placed on the role that the power exponent can play in the investigation and quantification of nonlinear pharmacokinetics and the elucidation of the underlying physiological processes. METHODS: Forty-one sets of concentration-time data were inferred from 20 published clinical trial studies, and 8 sets of area-under-the-curve (AUC) and maximum concentration (Cmax) values as a function of dose were collected. Both types of data were tested for a power law relationship using least squares regression analysis. RESULTS: Thirty-nine of the concentration-time curves were found to exhibit power law tails, and two dominant fractional exponents emerged. Short infusion times led to asymptotic tails with a single power exponent of - 1.57 +/- 0.14, while long infusion times resulted in steeper tails characterized by roughly twice the exponent. The curves following intermediate infusion times were characterized by two consecutive power laws; an initial short slope with the larger alpha value was followed by a crossover to a long-time tail characterized by the smaller Beta exponent. The AUC and Cmax parameters exhibited a power law dependence on the dose, with fractional power exponents that agreed with each other and with the exponent characterizing the shallow decline. Computer simulations revealed that a two- or three-compartment model with both saturable distribution and saturable elimination can produce the observed behaviour. Analogous linear models did not provide good fits over the range of values collected empirically. Furthermore, there is preliminary evidence that the nonlinear dose-dependence is correlated with the power law tails. CONCLUSIONS: Assessment of data from published clinical trials suggests that power laws accurately describe the concentration-time curves and nonlinear dose-dependence of paclitaxel, and the power exponents provide new\ insights into the underlying drug mechanisms. The interplay between two saturable processes can produce a wide range of behaviour, including concentration-time curves with exponential, power law, and dual power law tails.