Assessment of drug accumulation in the evaluation of pharmacokinetic data.

The evaluation of drug accumulation is approached from a practical point of view. Estimates of accumulation indices as obtained from standard estimators-AUC, peak levels, and trough levels (RAUAUC Rmax and Rmin, respectively)-are compared and differences analyzed. The estimators are based on the concentration-time curve characteristics area under the concentration-time curve (AUC), maximum concentration, and trough level. Simulated data are used for the analysis, both noise-free and with random error added. The data are based on pharmacokinetic parameters derived from a clinical study. The numerical procedures can be reproduced by the interested reader with little effort. It is shown empirically that if Rmin, > RAUC then simple kinetic behavior cannot be safely assumed, but accumulation is a complex function of time. Rmax as obtained from the data and an estimate of this value based on time to peak concentration (tmax) and apparent elimination rate constant (lambda(z)) after a single dose and at steady state can then be compared in an attempt to exclude time-dependent kinetics. This new numerical procedure can provide valuable and even pivotal information regarding the accumulation kinetics of a compound under investigation. Recommendations on how to use the available concentration-time information to the best advantage are presented. It is concluded that the assessment of drug accumulation should not be confined to the calculation of just one estimate, because the three estimators RAUC, Rmax. and Rmin reflect different aspects of accumulation. Moreover, all information about accumulation should be carefully analyzed in the clinical context. This way the relevant accumulation can be identified for safe and efficacious drug treatment.