Allometric scaling, estimation

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 the case of biopharmaceuticals, while two species are recommended, often times there is only one relevant species included in general preclinical safety studies because of species specificity. In either case, one or two species data are not sufficient to estimate the needed allometric terms. Therefore allometric scaling is not commonly used for biopharmaceuticals. There have... 

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... 

The use of half-life incorporates the variables that can influence the rate of drug elimination, those that affect distribution and clearance, whereas the use of systemic clearance focuses on the process of elimination, and corrections can be made for the extent of binding to plasma proteins and for estimated maximum life-span potential. Corrections seem to be justifiable when the human is included in the interspecies scaling technique. The necessity to apply correction factors, however, detracts from the use of allometric scaling for predicting the values of pharmacokinetic parameters. 

The values estimated by allometric scaling were compared with those observed in the single-dose human volunteer study (Table 8.5). We predicted that for compound X in humans, the plasma... 

Cosson et al. (54) provided another improvement for allometric scaling by using the PK/PD population approach. This approach enables one to use sparse and unbalanced data, which is most often the case in animal studies. Using this approach, they were able to estimate all allometric parameters and all interindividual variabilities in the population and for each species. An example of their code for implementation in NONMEM is presented in their publication (54). 

Similar to the techniques used for calculation of chemical disposition parameters, in vivo biotransformation kinetic parameters of a substrate can be estimated from in vitro systems such as microsomes, freshly isolated hepatocytes, fiver slices, and isolated perfused livers (24). Intrinsic clearance or Michaelis-Menten parameters for the whole liver can also be obtained by scaling in vitro parameters based on the cytochrome P450 enzyme content (25-27). These parameters can also be estimated from in vitro data obtained from recombinant human CYP systems, and also through allometric scaling of clearance estimates from animal PBPK models. 

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. 

Additional work may clarify whether this rather bleak assessment is entirely correct. While selection of a single index experiment is inconsistent with the observations made here, it is not difficult to propose the use of a median estimate derived from multiple bioassays. However, the optimmn procedure to foUow when there are bioassays available in two or more rodent species is not clear. Allometric scaling is ruled out by the obsawations, but estimation of a better (perhaps entirely empirical) replacement would substantially benefit from an updated examination of epidemiological data and incorporation of corresponding more recent, standardized, rodent bioassays. Extrapolation of intraspecies variability directly between species pairs appears impossible but that does not rule out the possibility of a relationship between species triples, nor the possibility of correlations with other endpoints. Even if no such extrapolation procedme can be devised, it is nevertheless possible to devise a probabilistic extrapolation that takes account of the lack of correlation. 

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... 

Predicted values were scaled from in vitro half-life data using liver microsomes and the well-stirred model of hepatic extraction. Hepatic Cl predictions were corrected for plasma and microsomal protein binding. Predicted total Cl was obtained by adding in renal Cl estimates which were, in turn, scaled allometrically (Y = aW015). 

To predict hepatic clearance of Compound X in man, human in vitro intrinsic clearance could then be scaled to hepatic clearance, using a technique that had been validated in the rat. Ashfortt et al 1995Renal clearance is subject to an allometric relationship and can generally be scaled across species (see below). The predicted in vivo renal Cl for the rat (estimated by multiplying the predicted hepatic Cl by 9) may be scaled allometrically to... 

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