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 <i>CL_iv</i>, clear disposition pathway and animal (rat, dog, monkey) <i>CL_iv</i> were analyzed. All drugs were stratified based on their disposition pathway, liver extraction ratio (<i>ER_H</i>) and ratios of unbound clearance to renal glomerular filtration rate (<i>R_GFR</i>). Up to 22 AS methods were applied and compared in prediction of human <i>CL_iv</i> to each group of drugs. 3. AS methods that give the best prediction of human <i>CL_iv</i>, were identified for drugs primarily eliminated through liver with a fraction of renal elimination (<i>f_renal</i>) within 0.3–0.5 or <i>ER_H</i> &gt; 0.3, where human <i>CL_iv</i> of more than 80% or 90% drugs could be accurately (within 2- or 3-fold error) predicted. For drugs with <i>ER_H</i> TS_R,D 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 <i>CL_iv</i>.