Allometric animal scaling

A hallmark of PB-PK models is the ability to scale up animal-based models to humans, thus allowing tissue drug concentrations to be predicted in the absence of data that are difficult or impossible to collect. Initial efforts to apply interspecies extrapolations to anticancer drugs have been greatly extended to chemical risk assessment based on PB-PK models [14]. Empirical allometric equations based on animal body weight have been the mainstay to scale organ weights and... 

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 ... 

Today, well over 100 biological parameters of mammals are known to be linearly related to body weight and highly predictable on an mterspecies basis (Davidson et al. 1986, Voisin et al. 1990, Calabrese et al. 1992). The allometric equation has traditionally been used for extrapolation of experimental data concerning physiological and biochemical functions from one mammalian species to another. In addition, the allometric equation has also been used extensively as the basis for extrapolation, or scaling, of e.g., a NOAEL derived for a chemical from studies in experimental animals to an equivalent human NOAEL, i.e., a correction for differences in body size between humans and experimental animals. 

As mentioned in Section 5.3.2.3, 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. With regard to inhalation of substances, which act systemically, the lower detoxification (metabolic) rate in larger animals is balanced by a lower uptake (lower respiratory rate) and thus no scaling factor is needed (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. 

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. 

For oral exposures, administered doses should be scaled from animals to humans on the basis of the caloric requirement approach (Section 5.3.2.3), i.e., body weight normalized by the 3/4 power. It is noted that the 3/4 power is consistent with current science, including empirical data that allow comparison of potencies in humans and animals, and it is also supported by analysis of the allometric variation of key physiological parameters across mammalian species. It is also noted that it is generally more appropriate at low doses, where sources of nonlinearity such as samration of enzyme activity are less likely to occur. 

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... 

Much has been published on the extrapolation of in vivo data from animals to humans. These include pharmacokinetic data (e.g. half-lives, plasma concentrations, clearances and rates of metabolism) and pharmacodynamic data (e.g. effective and toxic doses). Two excellent reviews present many examples and insightful discussions on isometric and allometric relationships, time scales, interspecies pharmacokinetic and pharmacodynamic scaling, and physiological models (Boxenbaum and D Souza, 1990 Chappell and Mordenti, 1991). 

Endothermic homeotherms are characterized by high mass-specific rates of oxygen consumption relative to similar-sized ectotherms. This difference can be shown by examining the allometric scaling relationship between rate of oxygen consumption (M) and body mass (IF). For ectothermic and endothermic animals, whole animal oxygen consumption rate is proportional to total body mass raised to approximately the 0.75 power ... 

First, if the compound was cleared mainly by hepatic metabolism in the animal species tested and if human hepatocytes in vitro suggest the same will be true in humans, then the measured hepatocyte clearance may be used in a process called in vitro/in vivo scaling (20, pp. 207-228) to provide an estimate of the human intrinsic clearance. The application of Equation 5 then gives an estimate of the human systemic clearance. Second, the animal PK parameters of CL and Vj can be subjected to allometric scaling (20, pp. 207-228) whereby the PK parameter is related to a measurable allometric variable such as body mass, body surface area, heart rate, and so forth. (21) by fitting these parameter-variable pairs for several species to an empirical power equation of the form... 

Khor SP, Amyx H, Davis ST, Nelson D, Baccanari DP, Spector T. Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics Allometric scaling of animal data, pharmacokinetics and toxicodynamics of 5-fluorouracil in humans. Cancer Chemother Pharmacol 1997 39 233-8. 

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