A unified strategy in selection of the best allometric scaling methods to predict human clearance based on drug disposition pathway.

1. It is critical to develop a unified strategy to select the best allometric scaling (AS) method for a given group of drugs. 2. A total of 446 drugs with known human CL, clear disposition pathway and animal (rat, dog, monkey) CL were analyzed. All drugs were stratified based on their disposition pathway, liver extraction ratio (ER) and ratios of unbound clearance to renal glomerular filtration rate (R). Up to 22 AS methods were applied and compared in prediction of human CL to each group of drugs. 3. AS methods that give the best prediction of human CL, were identified for drugs primarily eliminated through liver with a fraction of renal elimination (f) within 0.3-0.5 or ER > 0.3, where human CL of more than 80% or 90% drugs could be accurately (within 2- or 3-fold error) predicted. For drugs with ER < 0.3, acceptable accuracy could be achieved by a two species method TS resulting more than 60% or 75% drugs were predicted within 2- or 3-fold error. 4. By stratified analysis of drugs, according to their disposition pathway and organ extraction ratio, a unified strategy was developed to select the best AS method in prediction of human CL.