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

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 CL_iv, clear disposition pathway and animal (rat, dog, monkey) CL_iv were analyzed. All drugs were stratified based on their disposition pathway, liver extraction ratio (ER_H) and ratios of unbound clearance to renal glomerular filtration rate (R_GFR). Up to 22 AS methods were applied and compared in prediction of human CL_iv to each group of drugs.

3. AS methods that give the best prediction of human CL_iv, were identified for drugs primarily eliminated through liver with a fraction of renal elimination (f_renal) within 0.3–0.5 or ER_H > 0.3, where human CL_iv of more than 80% or 90% drugs could be accurately (within 2- or 3-fold error) predicted. For drugs with ER_H < 0.3, acceptable accuracy could be achieved by a two species method 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 CL_iv.

Keywords:

• Allometric scaling
• disposition pathway
• human clearance
• prediction

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