QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.016188v1 35/10/1886    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tang, H. Articles by Fluhler, E. Search for Related Content PubMed PubMed Citation Articles by Tang, H. Articles by Fluhler, E. Pubmed/NCBI databases Medline Plus Health Information Medicines

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

Bioanalytical R&D, Drug Safety and Metabolism, Wyeth Research, Pearl River, New York (H.T., A.H., M.L., E.F.); and Department of Pharmaceutical Sciences, College of Pharmacy, the University of Arizona, Tucson, Arizona (M.M.)

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). 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 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 · 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 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.

This article has been cited by other articles:

				N. A. Hosea, W. T. Collard, S. Cole, T. S. Maurer, R. X. Fang, H. Jones, S. M. Kakar, Y. Nakai, B. J. Smith, R. Webster, et al. Prediction of Human Pharmacokinetics From Preclinical Information: Comparative Accuracy of Quantitative Prediction Approaches J. Clin. Pharmacol., May 1, 2009; 49(5): 513 - 533. [Abstract] [Full Text] [PDF]

				R. Laufer, O. G. Paz, A. Di Marco, F. Bonelli, E. Monteagudo, V. Summa, and M. Rowley Quantitative Prediction of Human Clearance Guiding the Development of Raltegravir (MK-0518, Isentress) and Related HIV Integrase Inhibitors Drug Metab. Dispos., April 1, 2009; 37(4): 873 - 883. [Abstract] [Full Text] [PDF]

				K. Goteti, P. J. Brassil, S. S. Good, and C. E. Garner Estimation of Human Drug Clearance Using Multiexponential Techniques J. Clin. Pharmacol., October 1, 2008; 48(10): 1226 - 1236. [Abstract] [Full Text] [PDF]

				K. W. Ward, D. J. Coon, D. Magiera, S. Bhadresa, E. Nisbett, and M. S. Lawrence Exploration of the African Green Monkey as a Preclinical Pharmacokinetic Model: Intravenous Pharmacokinetic Parameters Drug Metab. Dispos., April 1, 2008; 36(4): 715 - 720. [Abstract] [Full Text] [PDF]