Allometric scaling of clearance in dogs.
Most drugs indicated for use in dogs are labeled for administration on a mg/kg basis. Such dosing recommendations are grounded on an assumption that total body clearance (Cl) scales in a manner directly proportional to body weight (i.e. that it scales with an allometric exponent of 1). Despite the critical nature of this assumption (the range of normal canine body weights can go from as small as 2 lbs to almost 200 lbs), the validity of this assumption has not been rigorously challenged. Therefore, this manuscript provides an initial assessment of the potential ramifications of this assumption. This objective was accomplished through the following three sets of analysis: (i) examining the observed vs. predicted Cl values across 10 drugs based upon interspecies scaling; (ii) estimating the difference in area under the concentration vs. time curve values if Cl scaled directly in proportion to body weight vs. in a manner consistent with the allometric exponent estimated in the first data analysis; and (iii) exploring the impact of breed differences in drug metabolism that may further confound the problem of exposure assessment. Based upon this assessment, we conclude that if Cl does not scale directly in proportion to body weight, the actual drug exposure in large or small dogs could differ markedly from those concentrations estimated on the basis of studies conducted in beagle-sized dogs.
Martinez
M
M
Division of Therapeutic Drugs for Food Animals (HFV-130), Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, USA. marilyn.martinez@fda.hhs.gov
Mahmood
I
I
Hunter
R P
RP
D000818:Animals; D001835:Body Weight; D004285:Dogs / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate / Q000502:physiology*; D011817:Rabbits; D013045:Species Specificity; D019155:Veterinary Drugs / Q000008:administration & dosage / Q000493:pharmacokinetics*
D019155:Veterinary Drugs