Recent data (Careau et al. 2007 ; Packard and Birchard 2008 ), however, question
the assumption that basal metabolic rate can be used as a universal scaling factor.
Despite its common usage in zoological medicine, this method has not been
validated, and several manuscripts have illustrated failures using this method
(Hunter et al. 2008 ; Jacobson 1996 ; Mahmood et al. 2006 ; Page et al. 1991 ;
Table 1 ). Furthermore, neither companion animal veterinarians nor pharmacolo-
gists employed in human pharmaceutical development use this method to determine
dosage regimens. In summary, there is no rationale published in the scientific
literature that validates the use of this method for dose selection.
2.3 Allometric Scaling
Allometric scaling builds on the definition of metabolic scaling in that pharmaco-
kinetic parameters, not simply the dose, are allometrically scalable. This method
shares the assumptions that species differences in pharmacodynamics are clinically
negligible and that the drug pharmacokinetics has a log–log (allometric) relation-
ship to weight. Although allometric scaling of pharmacokinetic parameters is
commonplace, little information is available for prediction of pharmacodynamic
parameters across species. A general expectation is that the rates of biological
turnover processes should obey basic allometric principles, while intrinsic capacity
and pharmacological sensitivity may or may not agree among species owing to
genetic and/or transductional differences (Lepist and Jusko 2004 ). Once key phar-
macokinetic parameters have been estimated, then standard dose calculations can
be made for the species to be treated.
Allometric scaling has become the method of choice for interspecies extrapola-
tion in the discovery and development of drugs for human use, specifically for
selecting the dose in the first human studies (Boxenbaum and DiLea 1995 ). This
application of scaling involves three to five species. Typically these would include
one rodent species (mouse or rat), a beagle dog, and a nonhuman primate species.
The established pharmacokinetic parameters in this limited number of species are
then used to predict human pharmacokinetic parameters, as well as intravenous first
dose for human phase I studies (Brodie and Reid 1967 ; Mahmood and Balian 1999 ;
Mahmood et al. 2003 ).
Subject Calculations Regimen
Polar bear (350 kg) K = 70 16.20.5 = 8.1
SMEC¼70 350^0 :^25
¼ 16 : 2 16.20.1 = 1.6 8 mg/kg q12h
Virginia opossum (2 kg) K = 49 41.20.5 = 21
SMEC¼49 2^0 :^25
¼ 41 : 2 41.20.1 = 4.1 20 mg/kg q6h
Ostrich (100 kg) K = 78 24.60.5 = 12.3
SMEC¼78 100^0 :^25
¼ 24 : 6 24.60.1 = 2.4 12 mg/kg q12h
Boa (10 kg)K= 10 5.60.5 = 2.8
SMEC¼10 10^0 :^25
¼ 5 : 6 5.60.1 = 0.5 3 mg/kg q48h
(Sedgwick 1993 )146 R.P. Hunter