Get access

Interspecies allometric scaling. Part I: prediction of clearance in large animals

Authors

  • I. MAHMOOD,

    1. Clinical Pharmacology and Toxicology Branch (HFD-579), Office of Drug Evaluation VI, Center for Drug Evaluation and Research
    Search for more papers by this author
    • 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.

  • M. MARTINEZ,

    1. Division of Therapeutic Drugs for Food Animals (HFV-130), Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food & Drug Administration, Rockville, MD
    Search for more papers by this author
    • 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.

  • R. P. HUNTER

    1. Elanco Animal Health, A Division of Eli Lilly and Company, Veterinary Safety/ADME, Greenfield, IN, USA
    Search for more papers by this author

Iftekhar Mahmood, 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 20852, USA. E-mail: mahmoodi@cder.fda.gov

Abstract

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. The knowledge of pharmacokinetics in veterinary species is important for dosage selection, particularly in the treatment of large zoo animal species, such as elephants, giant cats and camels, for which pharmacokinetic data are scant. Therefore, the accuracy in clearance predictions in large animal species, with and without the use of correction factors (rule of exponents), and the impact of species selection in the prediction of clearance in large animal species was examined. Based upon this analysis, it was determined that there is a much larger risk of inaccuracies in the clearance estimates in large animal species when compared with that observed for humans. Unlike in humans, for large animal species, correction factors could not be applied because there was no trend between the exponents of simple allometry and the appropriate correction factor for improving our predictions. Nevertheless, we did see an indication that the exponents of simple allometry may alert us as to when the predicted clearance in the large animal may be underestimated or overpredicted. For example, if a large animal is included in the scaling, the predicted clearance in a large animal should be considered overestimated if the exponent of simple allometry is >1.3. Despite the potential for extrapolation error, the reality is that allometric scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect target animal safety, therapeutic response, or the accuracy of withdrawal time predictions.

Ancillary