Abstract
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 CLiv, clear disposition pathway and animal (rat, dog, monkey) CLiv were analyzed. All drugs were stratified based on their disposition pathway, liver extraction ratio (ERH) and ratios of unbound clearance to renal glomerular filtration rate (RGFR). Up to 22 AS methods were applied and compared in prediction of human CLiv to each group of drugs.
3. AS methods that give the best prediction of human CLiv, were identified for drugs primarily eliminated through liver with a fraction of renal elimination (frenal) within 0.3–0.5 or ERH > 0.3, where human CLiv of more than 80% or 90% drugs could be accurately (within 2- or 3-fold error) predicted. For drugs with ERH < 0.3, acceptable accuracy could be achieved by a two species method TSR,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 CLiv.
Declaration of interest
The study was supported by the “12th Five-year” National Key Technology R&D Program of China (Ministry of Science and Technology of the People’s Republic of China; No. 2012ZX09303006-002) and the National Natural Science Foundation of China (No. 81403013).
Supplementary material available online