Interspecies scaling

Peptides and proteins exhibit distinct species specificity with regard to structure and activity. Peptides and proteins with identical physiological function may have different amino acid sequences in different species, and may have no activity or be even immunogenic if used in a different species. 

The extrapolation of animal data to predict pharmacokinetic parameters by allo-metric scaling is an often-used tool in drug development, with multiple approaches available at variable success rates [99-101]. In the most frequently used approach, pharmacokinetic parameters between different species are related via body weight using a power function  

For most traditional small-molecule drugs, allometric scaling is often imprecise, especially if hepatic metabolism is a major elimination pathway and/or if there are interspecies differences in metabolism. For peptides and proteins, however, allometric scaling has frequently proven to be much more precise and reliable, 

In a study investigating the allometric relationships of pharmacokinetic parameters for five therapeutic proteins, the allometric equations for clearance and volumes of distribution, however, were found to be different for each protein [102]. This variability was attributed to possible species specificity and immune-mediated clearance mechanisms. Species specificity refers to the inherent differences in structure and activity across species. Minute differences in the amino acid sequence may render an agent inactive when administered to foreign species, and may even generate an immunogenic response. Immunogenicity has been clearly demonstrated in a study with the tumor necrosis factor receptor-immunoglobulin fusion protein lenercept. This all-human sequence protein elicits an immune response in laboratory animals which ultimately results in the rapid clearance of the protein [103]. 

1 Meibohm, B., and H. Derendorf. 2002. Pharmacokinetic/pharmacodynamic studies in drug product development. 

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Patel BA, Boudinot FD, Schinazi RF, Gallo JM, Chu CK (1990) Comparative pharmacokinetics and interspecies scaling of 3 -azido-3 -deoxythymidine (AZT) in several mammalian species. J Pharmacobiodyn 13 206-211... 

Lin, J.H., Applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics, Drug Metab. Dispos. 26(12), 1202-1212, 1998. 

Mahmood, I., Balian, J. D., Interspecies scaling a comparative study for the prediction of clearance and volume using two or more species, Life Sci. 1996, 59, 579—585. 

Jezequel, S. G., Fluconazole interspecies scaling and allometric relationships of pharmacokinetic properties, J. Pharm. Pharmacol. 1994, 46, 196-199. 

Mahmood, I., Interspecies scaling of renally secreted drugs, Life Sd. 1998, 63, 2356-2371. 

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

Raabe, O.G., L.S. Rosenblatt, and R.A. Schlenker. 1990. Interspecies scaling of risk for radiation-induced bone cancer. Inter. Jour. Radiation Biol. 57 1047-1061. 

Table 8.5 Selected potencies, or cancer slope factors, used by the US EPAd For those based on animal data, the potencies include a factor for interspecies scaling (see text)...

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. 

Holleran, J.L. et al. (2005) Plasma pharmacokinetics, oral bioavailabihty, and interspecies scaling of the DNA melhyltransferase inhibitor, zebularine. Clinical Cancer Research, 11, 3862-3868. 

Ritschel, W. A., Vachharajani, N. N., Johnson, R. D., and Hussain, A. S. (1992). The allo-metric approach for interspecies scaling of pharmacokinetic parameters. Comp. Biochem. Physiol. C 103 249-253. 

TOO Mahmood, I. 2002. Interspecies scaling predicting oral clearance in humans. Am.J. Ther. 9 35-42. 

Boxenbaum, H. 1982. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. 

B. L. Ferraiolo, and J.D. Green. 1991. Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm. Res. 8 1351— 1359. 

Hayakawa H, Fukushima Y, Kato H, et al. Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters. Drug Metab Dispos 2003 31 1409-1418. 

Mordenti J, Chen S, Moore J, Ferraiolo B. Interspecies scaling of clearance data for five recombinant proteins. Pharmaceut Res 1991 8 1351-9. 

Mahmood J (2000) Interspecies Scaling Role of Protein Binding in the Prediction of Clearance from Animals to Humans. J Clin Pharmacol 40 1439-1446... 

Gamer RC, Barker J, Flavell C et al. (2000) A validation study comparing accelerator MS and liquid scintillation counting for analysis of 14C-labelled drugs in plasma, urine and faecal extracts. J Pharm Biomed Anal 24 197-209 Hayakawa H, Fukushima Y, Kato H et al. (2003) Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters. Drug Metab Dispos 31 1409-1418... 

Mahmood I, Balian JD. Interspecies scaling Predicting clearance of drugs in humans. Three different approaches. Xenobiotica 1996 26 887-95. 

Well-known macromolecules that have been approved and are currently marketed are listed in Table 32.1. This chapter presents information on mABs currently marketed or under investigation and discusses methodology used to assay macromoleculeS/ interspecies scaling of macromoleculeS/ pharmacokinetic (PK) characteristics of macromoleculeS/ and pharmacodynamics (PD) of macromolecules. 

As discussed in Chapter 30 and elsewhere (13), interspecies scaling is based upon allometry (an empirical approach) or physiology. Protein pharmacokinetic parameters such as volume of distribution (Pd), elimination half-life (b/2)/ and elimination clearance (CL) have been scaled across species using the standard allometric equation (14) ... 

In spite of the limitations/ interspecies scaling can be used to relate dosages across species in toxicology studies/ to predict human PK parameter estimates for macromoleculeS/ and/ as discussed in Chapters 30 and 31/ to guide dose selection in Phase I clinical trials. An understanding of the characteristics of the macromolecule is important for the interpretation and application of these results. 

Mordent J, Osaka G, Garcia K, Thomsen K, Licko V, Meng G. Pharmacokinetics and interspecies scaling of recombinant human factor VIII. Toxicol Appl Pharmacol 1996 136 75-8. 

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