Estimation of the absorption rate constant for a drug subject to non-linear elimination: Comparison on non-linear regression and the Cmax, Tmax approach

Abstract

A method was developed for calculating the absorption rate constant (k_a) of drugs whose elimination involves a capacity-limited process. Pidgeon and Pitlick reported a method for calculating k_a of drugs whose disposition obeys a first-order rate process. Their method obviates the need for large numbers of samples in the absorption phase and is less influenced by errors in data points prior to the maximum plasma concentration where the rate of change of concentration is rapid and error is likely. In the present study, a method for calculating the absorption rate constant of drugs whose elimination involves a capacity-limited process was designed based on Pidgeon and Pitlick's method, and the method was tested on theoretical data. On the comparison of k_a obtained by nonlinear least-squares analysis with that obtained by the present method, the overall correlation for the fits obtained by non-linear least-squares analysis was superior. On the other hand, on the theoretical data (without error), the present method gave less percentage error in calculated k_a, and a good correlation was obtained for the fits. Consequently, for the calculation of k_a of drugs whose elimination involves Michaelis-Menten metabolism, the present method is convenient when relatively few sample points are available in the absorption phase.