ASSESSMENT OF DRUG ACCUMULATION IN THE EVALUATION OF PHARMACOKINETIC DATA

The evaluation of drug accumulation is approached from a practical poi nt of views. Estimates of accumulation indices as obtained from standa rd estimators-AUC, peak levels, and trough levels (R-AUC, R-max, and R -min, respectively)- -are compared and differences analyzed. The estim ators are based on the concentration-time curve characteristics area u nder the concentration-time curve (AUC), maximum concentration, and tr ough level. Simulated data are used for the analysis, both noise-free and with random error added. The data are based on pharmacokinetic par ameters derived from a clinical study. The numerical procedures can be reproduced by the interested reader with little effort. If is shown e mpirically that if R-min > R-AUC then simple kinetic behavior cannot b e safely assumed, bur accumulation is a complex function of time. R-ma x as obtained from the data and all estimate of this value based on ti me to peak concentration (t(max)) and apparent elimination rate consta nt (lambda(z)) after a single dose and at steady state can then be com pared in an attempt to exclude lime-dependent kinetics. This new numer ical procedure can provide valuable and even pivotal information regar ding the accumulation kinetics of a compound under investigation. Reco mmendations on how to use the available concentration-time information to the best advantage are presented. It is concluded that the assessm ent of drug accumulation should not be confined to the calculation of just one estimate, because the three estimators R-AUC, R-max, and R-mi n reflect different aspects of accumulation. Moreover, all information about accumulation should be carefully analyzed in the clinical conte xt. This way the relevant accumulation can be identified for safe and efficacious drug treatment. Journal of Clinical Pharmacology: 1998;38: 680-684 (C) 1998 The American College of Clinical Pharmacology.