Interspecies allometric scaling: prediction of clearance in large animal species: Part II: mathematical considerations M. MARTINEZ* 1 I. MAHMOOD  1 & R. P. HUNTER à *Division of Therapeutic Drugs for Food Animals (HFV-130), Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food & Drug Administration, Rockville;   Clinical Pharmacology and Toxicology Branch (HFD-579). Office of Drug Evaluation VI. Center for Drug Evaluation and Research. Food & Drug Administration, Woodmont Office Center II, Rockville, MD; à Elanco Animal Health, A Division of Eli Lilly and Company, Greenfield, IN, USA Martinez, M., Mahmood, I., Hunter, R. P. Interspecies allometric scaling: pre- diction of clearance in large animal species: Part II: mathematical considera- tions. J. vet. Pharmacol. Therap. 29, 425–432. Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. However, it is important to appreciate the mathematical underpinnings of this scaling procedure when using it to predict pharmacokinetic parameter values across animal species. When cautiously applied, allometry can be a tool for estimating clearance in veterinary species for the purpose of dosage selection. It is particularly valuable during the selection of dosages in large zoo animal species, such as elephants, large cats and camels, for which pharmacokinetic data are scant. In Part I, allometric predictions of clearance in large animal species were found to pose substantially greater risks of inaccuracies when compared with that observed for humans. In this report, we examine the factors influencing the accuracy of our clearance estimates from the perspective of the relationship between prediction error and such variables as the distribution of body weight values used in the regression analysis, the influence of a particular observation on the clearance estimate, and the ‘goodness of fit’ (R 2 ) of the regression line. Ultimately, these considerations are used to generate recommendations regarding the data to be included in the allometric prediction of clearance in large animal species. (Paper received 31 May 2005; accepted for publication 12 July 2006) Marilyn Martinez, Division of Therapeutic Drugs for Food Animals (HFV-130), Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food & Drug Administration, 7500 Standish Place, Rockville, MD 20855, USA. E-mail: mmartin1@cvm.fda.gov INTRODUCTION Within the published literature, there are numerous examples of studies that use published pharmacokinetic data to estimate the allometric relationship between a parameter such as clearance or volume of distribution vs. body weight (W). In this regard, among its uses, it is especially important for estimating an appropriate dose in large animal species for which there does not exist pharmacokinetic or clinical information to support dose estimation (Hunter & Isaza, 2002; Isaza & Hunter, 2004). It is also used to predict a terminal elimination half-life value, which may be applied by extension services such as the FARAD (http://www. farad.org) for estimating withdrawal times when drugs are administered to food-producing animals in an extralabel manner (Craigmill & Cortright, 2002). Similar to its use for selecting the first time dose in humans (Boxenbaum & DiLea, 1995), interspecies extrapolation serves an important function within the framework of veterinary medicine. While it is now well-established that clearance can be extrapolated from small laboratory animals to man with a fair degree of accuracy, provided the rule of exponents is used (Mahmood & Balian, 1996), it is not known if the clearance from small animals can be extrapolated to large animals with the same degree of accuracy. Despite numerous examples of the successful applica- tion of allometric scaling (Mordenti, 1986; Hu & Hayton, 2001), there are also examples of its failure to accurately predict drug pharmacokinetics across species (Riviere et al., 1997). 1 The views expressed in this article are those of the authors and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred. J. vet. Pharmacol. Therap. 29, 425–432, 2006. Journal compilation Ó 2006 Blackwell Publishing Ltd. No claim to original US government works 425