Interspecies extrapolation allometric 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... 

Kalberlah and Schneider (1998) have analyzed the information on the quantification of extrapolation factors. They noted that in interspecies extrapolation, two variables must be differentiated The systematic differences between different species, and the variability in the sensitivity of the species. Systematic differences can, e.g., be recorded by means of allometric approaches, scaling (Section 5.3.2). The reasons for the variability in sensitivity may be due to both toxicokinetic and toxicodynamic characteristics of a species. 

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. 

I also (Crouch 1996) evaluated the data of Gold et al. (see above) while illustrating the use of uncertainty distributions for interspecies extrapolations, but used the multistage model (rather than the one-hit model used to derive TDsqs) and a different adjustment to a standard lifetime. I demonstrated the lognormality of rat-to-mouse, mouse-to-hamster, and hamster-to-rat interspecies ratios of a carcinogenic potency parameter, and I also demonstrated that the available information was inconsistent with allometric scaling between these rodents with any power law. 

These results challenge some current default approaches to interspecies extrapolation used for risk assessment. In particular, the selection of index animal experiment(s) on which to base the estimation of carcinogenic potency is inconsistent with the observation that there are lognormal distributions of CDio for each chemical in each animal species in fact, no one experiment can be singled out as representative in snch circumstances. Furthermore, the use of allometric scaling for extrapolating quantitative carcinogenicity measures from animals to humans is not supported by the observations in animals, nor the Umited informalion on humans. 

Allometric scaling is a method of interspecies extrapolation that is commonly used to estimate human PK parameters from PK parameters measured in animals. It makes use of the fact that many physiological parameters of different species can be empirically related to the relative size of the species (usually body weight, but other parameters such as the relative size of particular organs can also be useful for some parameters). The result is that PK parameter values (represented here by Y) for different species can often be correlated with species body weight (BW) by an equation of the form... 

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). 

---