Development of a Novel Method for Predicting Human Volume of Distribution at Steady-State of Basic Drugs and Comparative Assessment With Existing Methods

The parameters characterizing tissue distribution refer to the tissue/plasma partition coefficients (Kp), which can be used to derive volume of distribution at steady-state (V-ss). The effort for predicting drug distribution in human has been further expanded to calculation methods using in vitro-based algorithms. The objective of the present study was to develop a novel prediction method to estimate human V-ss for moderate-to-strong bases. The predictive performance of the novel method was compared with other well established in vitro-based methods available in the literature. Relevant information collected from previous prediction studies of V-ss facilitated the development of the novel method. This was based on the calculation of V-ss from data on Kp, which were estimated by correlating the unbound tissue/plasma ratio in vivo (Kpu) with the unbound red blood cells partitioning (RBCu) determined in vitro. The comparative assessment of the novel correlation method with existing prediction methods of human V-ss was done using a literature dataset of 61 basic drugs (at least one pK(a) >= 7). The five existing Vs. prediction methods published in the literature are comprised of four versions of tissue composition-based models along with the model of Lombardo using the principle of Oie-Tozer. The statistical analysis of the prediction performance indicated that the novel method demonstrated a greater degree of accuracy compared to all other published methods. The maximum percentage of predicted values that fall within a twofold-error range is 77% for the basic drugs tested. Overall, the present study describes the development and the assessment of the predictive performance of the novel prediction method of human V-ss based upon in vitro data, which appears to be superior based on the current dataset studied for basic drugs. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4941-4961, 2009