Received for publication April 10, 2007.
Revised July 18, 2007.
Accepted for publication July 19, 2007.

Interspecies Prediction Of Human Drug Clearance Based on Scaling Data From One Or Two Animal Species

Abstract

A data-driven approach was adopted to derive new one- and two-species-based methods for predicting human drug clearance (CL) using CL data from rat, dog, or monkey (n=102) (Jolivette and Ward, 2005). The new one-species methods were developed as: CL_human/kg = 0.152·CL_rat/kg; CL_human/kg = 0.410·CL_dog/kg; and CL_human/kg = 0.407·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 to 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 ·W_human^0.628 (referred to as rat-dog method) and CL_human = a_rat-monkey·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 to 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 to 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.

Key words: drug clearance, pharmacokinetic modeling, pharmacokinetics

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