Interspecies Prediction of Human Drug Clearance Based on Scaling Data from One or Two Animal Species

Abstract

ABSTRACT:A data-driven approach was adopted to derive new one-and twospecies-based methods for predicting human drug clearance (CL) using CL data from rat, dog, or monkey (n ‫؍‬ 102). The new onespecies methods were developed as CL human /kg ‫؍‬ 0.152 ⅐ CL rat /kg, CL human /kg ‫؍‬ 0.410 ⅐ CL dog /kg, and CL human /kg ‫؍‬ 0.407 ⅐ CL monkey / kg, referred to as the rat, dog, and monkey methods, respectively. The coefficient of the monkey method (0.407) was similar to that of the monkey liver blood flow (LBF) method (0.467), whereas the coefficients of the rat method (0.152) and dog method (0.410) were considerably different from those of the LBF methods (rat, 0.247; dog, 0.700). The new rat and dog methods appeared to perform better than the corresponding LBF methods, whereas the monkey method and the monkey LBF method showed improved predictability compared with the rat and dog one-species-based methods and the allometrically based "rule of exponents" (ROE). The new two-species methods were developed as CL human ‫؍‬ a rat-dog ⅐ W human 0.628 (referred to as rat-dog method) and CL human ‫؍‬ a rat-monkey ⅐ W human 0.650 (referred to as rat-monkey method), where a rat-dog and a rat-monkey are the coefficients obtained allometrically from the corresponding two species. The predictive performance of the two-species methods was comparable with that of the three-species-based ROE. Twenty-six Wyeth compounds having data from mouse, rat, dog, monkey, and human were used to test these methods. The results showed that the rat, dog, monkey, rat-dog, and rat-monkey methods provided improved predictions for the majority of the compounds compared with those for the ROE, suggesting that the use of three or more species in an allometrically based approach may not be necessary for the prediction of human exposure.

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

“…This value was derived from the observation that basal metabolic rates and passive renal filtration could be scaled by body weight with an exponent of 0.75. This has been qualified by several groups in the interspecies scaling for prediction of small molecule drug CL 33 , 34 . Given the mechanisms of CL of small molecules are governed by oxidative metabolism and renal CL, an exponent of 0.75 makes sense.…”

Upcyte Human Hepatocytes: a Potent In Vitro Tool for the Prediction of Hepatic Clearance of Metabolically Stable Compounds

“…8), and the root mean squared error (RMSE; eq. 9) were estimated as measures of bias, accuracy, and precision, respectively (Ito and Houston, 2004;Tang et al, 2007), for each set of predictions.…”

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

“…Our data therefore raise well recognized issues relating to the choice of pre-clinical species for undertaking human PK predictions as well as the most appropriate allometric method for interspecies scaling [33][34][35][36][37]. The tendency for predictions of human CL to be over estimated by allometric scaling has been noted previously for several established drugs [34] and more recently for new chemical entities in microdose investigations [32].…”