Prediction of volume of distribution in preclinical species and humans: application of simplified physiologically based algorithms.

The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict Vss and interspecies scaling factors to predict tissue-Kp s which require minimum input parameters, diminish the computing complexity and have better predictability. Vss of 86 structurally diverse compounds in preclinical species and 27 compounds in humans were predicted using only lung- and muscle-Kp as inputs. Interspecies scaling factor (s) were developed based on fold-differences in individual tissue lipid contents, relative organ blood flow: relative organ weight ratio between two species. Tissue-Kp s were predicted for 34 compounds using the newly developed interspecies scaling factors. The predicted-to-experimental Vss values for all the 113 compounds was 1.3 ± 0.9 with 83% values being within a factor of two. The tissue-Kp s in rat, dog and human were predicted using experimental tissue-Kp data in rodents and interspecies scaling factors and here also, 83% of tissue-Kp s were within two-fold of the experimental values. In conclusion, simplified physiologically based algorithms have been developed to predict both volume of distribution and tissue-Kp s, in which required input parameters as well as computing complexity have been noticeably reduced.