Scaling allometric

Much of the inter-species variation in pharmacokinetic properties can be explained as a consequence of body size (allometry). Consequently it is possible to scale pharmacokinetic parameters to the organism s individual anatomy, biochemistry and/or physiology in such a manner that differences between species are nuUified. Several excellent reviews on allometric scaling are available in the literature [2-7]. Allometric relationships can be described by an equation of the general form  

Where A is the coefficient (i.e. the intercept on the y-axis of logarithmically transformed data), BW is the body weight and a is the power function (slope of the Hne). 

When considering volume of distribution, an allometric relationship is not surprising as this value will be dependent upon the relative affinity for tissue compared to 

The value of 0.98 for the allometric exponent is so close to unity as to make the volume of distribution directly proportional to body weight, i.e. weight normalized volume is an invariant parameter (see Table 9.1). The mean value for the volume of distribution in the eight species is 0.82 0.21 L kg  

In cases where plasma protein binding varies across the species, allometric scaling should be based upon the volume of distribution of unbound drug. The considerably 

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West GB, Woodruff WH, Brown JH. Allometric scaling of metabolic rate from molecules and mitochondria to cells and mammals. Proc Natl Acad Sci USA 2002 99 Suppl 1 2473-8. 

The limitations of allometric scaling led us to investigate the method of effect scaling as an alternative strategy for matching equivalent doses of MDMA in rats and humans. In this approach,... 

A recent debate on allometric scaling has suggested that a great deal of further work is necessary before allometry can be used with confidence in a prospective... 

Lave, T., Coassolo, P., Reigner, B., Prediction of hepatic metabolic clearance based on interspecies allometric scaling techniques and in vitro-in vivo correlations, Clin. Pharmacokinet. 1999, 36, 211-321 and references cited therein. 

Bonate, P. L., Howard D., Critique of prospective allometric scaling does the emperor have clothes J. Clin. Pharmacol. 2000, 40, 335—340. 

Prediction methods based on animal pharmacokinetic data can be categorized into three types (1) allometric scaling, (2) proportionality methods, and (3) correlative approaches. All three make a basic underlying assumption that the types... 

A recent variation on the prediction of human VD using allometric scaling involves the use of what has been termed "fractal volume of distribution (vf) [7], This refers to the VD value corrected to within the bounds of actual volumes within the body - in the case of human the upper and lower bounds would be 70 1 and plasma volume, respectively. Thus, even if a compound were to have a VDSS of 1000 1, its Vf would be 69.8 1. The authors of this approach have shown that Vf scales allometrically across species better than VD [8], with the explanation that body volume and body mass are exactly scaleable across species. Animal values for Vf are calculated from VD obtained from pharmacokinetic studies using the relationship ... 

It is important to note that extrapolation using allometric scaling based on metabolic rate assumes that the parent compound is the toxic agent and that the detoxification is related to the metabolic rate and thus controls the tissue level. This is relevant for oral exposure only (ECETOC 2003). 

For substances with local effects on the respiratory tract, no general approach for interspecies scaling can be given. Anatomical and physiological differences in the airways between experimental animals and humans contribute to interspecies differences in local effects observed between animals and humans, see Section 4.7.8. It should be noted, however, that for local effects the determining factor for effects to occur in the respiratory tract is generally the concentration of the chemical in the air rather than the total dose and thus allometric scaling is not relevant. 

Vermeire et al. (1999) have assessed the remaining interspecies uncertainty, i.e., the uncertainty not related to differences in metabolic size that can be accounted for by allometric scaling (Section 5.3.3). A reanalysis and extension of the database was published a few years later (Rennen et al. 2001, Vermeire et al. 2001). The reanalyses indicated that the default factor of 3 for remaining uncertainty, as well as the traditional factor of 10 for interspecies differences in general, in many cases does not sufficiently account for the remaining interspecies differences. 

ECETOC (2003) recommended that in the absence of any substance- or species-specific mechanism or PBPK modeling (Section 4.3.6), allometric seating based on metabolic rate (W° ) (caloric requirement approach. Section 5.3.2.3) is considered to provide an appropriate default for an assessment factor for interspecies differences with respect to systemic effects. Allometric scaling was stated as being a tool for estimating interspecies differences of internal exposure or body burden and to provide indirectly information on differences in sensitivity between species. Typical scaling factors for interspecies adjustment were noted as 7 for mouse, 4 for rat, and 2 for dog however. 

In conclusion, if no substance-specific data are available, it is recommended as a default to correct for differences in metabolic size (differences in body size between humans and experimental animals) by using allometric scaling based on the caloric requirement approach (see Table 5.4). The assessment factor accounting for remaining interspecies differences should preferentially be described probabilistically as suggested by Vermeire et al. (1999, 2001) and KEMI (2003), or a deterministic default factor of 2.5 could be used for extrapolation of data from rat studies to the human situation. 

Pharmacokinetics and metabolism - absorption, distribution, metabolism and excretion (ADME), including potential for interactions, polymorphisms of drug metabolising enzymes and exposures in man predicted from interspecies allometric scaling... 

Finally, no discussion of human pharmacokinetic predictions is complete without a consideration of allometric scaling [67-69]. In general, allometry is the examination of relationships between size and function and it has been applied to the prediction of human pharmacokinetic parameters from animal pharmacokinetic parameters for decades [70]. Allometry has been shown to work reasonably well for predicting human VD from animal VD data, probably because volumes of plasma and various tissue across species are allometrically scaleable to body weight, a notion reinforced... 

Caldwell, G.W., Masucci, J.A., Yan, Z. and Hageman, W. (2004) Allometric scaling of pharmacokinetic parameters in drug discovery Can human CL Vss and tl/2 be predicted from in-vivo rat data European Journal of Drug Metabolism and Pharmacokinetics, 29, 133-143. 

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