Abstract
Sixty-one sets of clearance (CL) values in animal species were allometrically scaled for predicting human clearance. Unbound fractions (fu) of drug in plasma in rats and humans were obtained from the literature. A model was developed to predict human CL: CL = 33.35 ml/min × (a/Rfu)0.770, where Rfu is the fu ratio between rats and humans and a is the coefficient obtained from allometric scaling. The new model was compared with simple allometric scaling and the “rule of exponents” (ROE). Results indicated that the new model provided better predictability for human values of CL than did ROE. It is especially significant that for the first time the proposed model improves the prediction of CL for drugs illustrating large vertical allometry.
Footnotes
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↵2 The proposed model (eq. 5) was tested using one example of large vertical allometry (reboxetine), whose data were available to the authors during the revision of the manuscript. We predicted an Rfu greater than 5 for reboxetine. The data kindly provided by one of the reviewers (courtesy of Pfizer, Inc.) showed fu values of 0.17 and 0.02 in rats and humans, respectively, which translate to an Rfu of 8.5. Prediction of human CL based upon eq. 5 resulted in a PE of 104%, compared with 1395% and 804% based upon simple allometry and the ROE method, respectively.
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This work was presented at the American Association of Pharmaceutical Scientists Annual Meeting, Salt Lake City, Utah, October 26, 2003.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.004143.
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ABBREVIATIONS: CL, clearance; Rfu, ratio of unbound fraction in plasma between rats and humans; MLP, maximum life-span potential; BrW, brain weight; ROE, rule of exponents; PE, percentage error; GV150526A, sodium 4,6-dichloro-3-[(E)-3-(N-phenyl)propenamide]indole-2-carboxylate; PK, pharmacokinetic.
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↵1 Current address: Bioanalytical Department, Wyeth Research, Pearl River, New York.
- Received February 9, 2005.
- Accepted June 2, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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A NOVEL MODEL FOR PREDICTION OF HUMAN DRUG CLEARANCE BY ALLOMETRIC SCALING
