Performance characteristics of the adjusted r2 algorithm for determining the start of the terminal disposition phase and comparison with a simple r2 algorithm and a visual inspection method

Abstract

The adjusted r² algorithm is a popular automated method for selecting the start time of the terminal disposition phase (t_z ) when conducting a noncompartmental pharmacokinetic data analysis. Using simulated data, the performance of the algorithm was assessed in relation to the ratio of the slopes of the preterminal and terminal disposition phases, the point of intercept of the terminal disposition phase with the preterminal disposition phase, the length of the terminal disposition phase captured in the concentration-time profile, the number of data points present in the terminal disposition phase, and the level of variability in concentration measurement. The adjusted r² algorithm was unable to identify t_z accurately when there were more than three data points present in a profile's terminal disposition phase. The terminal disposition phase rate constant (λ_z ) calculated based on the value of t_z selected by the algorithm had a positive bias in all simulation data conditions. Tolerable levels of bias (median bias less than 5%) were achieved under conditions of low measurement variability. When measurement variability was high, tolerable levels of bias were attained only when the terminal phase time span was 4 multiples of t_1/2 or longer. A comparison of the performance of the adjusted r² algorithm, a simple r² algorithm, and t_z selection by visual inspection was conducted using a subset of the simulation data. In the comparison, the simple r² algorithm performed as well as the adjusted r² algorithm and the visual inspection method outperformed both algorithms. Recommendations concerning the use of the various t_z selection methods are presented.

Keywords: adjusted r2 algorithm; noncompartmental data analysis (NCA); pharmacokinetics; terminal disposition phase.