Abstract
The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immuno-globulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the pre-clinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.
Similar content being viewed by others
REFERENCES
T. A. McMahon and J. T. Bonner. On Size and Life, Scientific American Books, New York, 1983.
W. A. Calder III. Size, Function, and Life History, Harvard University Press, Cambridge, MA, 1984.
K. Schmidt-Nielsen. Scaling: Why Is Animal Size So Important? Cambridge University Press, New York, 1984.
H. Boxenbaum and R. W. D'Souza. Interspecies pharmacokinetic scaling, biological design, and neoteny. In B. Testa (eds.), Advances in Drug Research, Vol. 19, Academic Press Limited, London, 1990, pp. 139–196.
H. Boxenbaum. Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm. Drug Metab. Rev. 15:1071–1121 (1984).
J. Mordenti and W. Chappell. The use of interspecies scaling in toxicokinetics. In A. Yacobi, J. Skelly, and V. Batra (eds.), Toxicokinetics in New Drug Development, Pergamon Press, Elmsford, NY, 1989, pp. 42–96.
W. R. Chappell and J. Mordenti. Extrapolation of toxicological and pharmacological data from animals to humans. In B. Testa (ed.), Advances in Drug Research, Vol. 20, Academic Press, San Diego, 1991, pp. 1–116.
H. Boxenbaum. Interspecies scaling, allometry, physiological time and the ground plan of pharmacokinetics. J. Pharmacokinet. Biopharm. 10:201–227 (1982).
Q. J. Sattentau and R. A. Weiss. The CD4 antigen: Physiological ligand and HIV receptor. Cell 52:631–633 (1988).
C. A. J. Janeway. Accessories or coreceptors? Nature 335:208–210 (1988).
P. J. Maddon, A. G. Dalgleish, J. S. McDougal, P. R. Clapham, R. A. Weiss, and R. Axel. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47:333–348 (1986).
D. H. Smith, R. A. Byrn, S. A. Marsters, T. Gregory, J. E. Groopman, and D. J. Capon. Blocking of HIV-1 infectivity by soluble, secreted form of the CD4 antigen. Science 238:1704–1707 (1987).
R. A. Byrn, I. Sekigawa, S. M. Chamow, J. S. Johnson, T. J. Gregory, D. J. Capon, and J. E. Groopman. Characterization of in vitro inhibition of human immunodeficiency virus by purified recombinant CD4. J. Virol. 63:4370–4375 (1989).
R. Harris, S. Chamow, T. Gregory, and M. Spellman. Characterization of a soluble form of human CD4: Peptide analyses confirm the expected amino acid sequence, identify glycosylation sites, and demonstrate the presence of three disulfide bonds. Eur. J. Biochem. 188:291–300 (1990).
M. W. Spellman, C. K. Leonard, L. J. Basa, I. Gelineo, and H. van Halbeek. Carbohydrate structures of recombinant soluble human CD4 expressed in Chinese hamster ovary cells. Biochemistry 30:2395–2406 (1991).
D. J. Capon, S. M. Chamow, J. Mordenti, S. A. Marsters, T. Gregory, H. Mitsuya, R. A. Byrn, C. Lucas, F. M. Wurm, J. E. Groopman, S. Broder, and D. H. Smith. Designing CD4 immunoadhesins for AIDS therapy. Nature 337:525–531 (1989).
R. J. Harris, K. L. Wagner, and M. W. Spellman. Structural characterization of recombinant CD4-IgG hybrid molecule. Eur. J. Biochem. 194:611–620 (1990).
R. A. Byrn, J. Mordenti, C. Lucas, D. Smith, S. A. Marsters, J. S. Johnson, P. Cossum, S. M. Chamow, F. M. Wurm, T. Gregory, J. E. Groopman, and D. J. Capon. Biological properties of CD4 immunoadhesin. Nature 344:667–670 (1990).
V. Johnson and T. Maack. Renal extraction, filtration, absorption, and catabolism of growth hormone. Am. J. Physiol. 233:F185–F196 (1977).
G. Baumann, M. W. Stolar, K. Amburn, C. P. Barsano, and B. C. DeVries. A specific growth hormone-binding protein in human plasma: Initial characterization. J. Clin. Endocrinol Metab. 62:134 (1986).
A. C. Herington, S. Ymer, and J. Stevenson. Identification and characterization of specific binding proteins for growth hormone in normal human sera. J. Clin. Invest. 77:1817–1823 (1986).
G. Baumann, K. D. Amburn, and T. A. Buchanan. The effect of circulating growth hormone-binding protein on metabolic clearance, distribution, and degradation of human growth hormone. J. Clin. Endocrinol. Metab. 64:657–660 (1987).
G. Baumann, K. Amburn, and M. A. Shaw. The circulation growth hormone (GH)-binding protein complex: A major constituent of plasma GH in man. Endocrinology 122:976 (1988).
D. Collen, E. J. Topol, A. J. Tiefenbrunn, H. K. Gold, M. L. Weisfeldt, B. E. Sobel, R. C. Leinbach, J. A. Brinker, P. A. Ludbrook, I. Yasuda, B. H. Bulkey, A. K. Robison, A. M. Hutter, W. R. Bell, J. J. Spadaro, B. A. Khaw, and E. B. Grossbard. Coronary thrombosis with recombinant human tissue-type plasminogen activator: A prospective, randomized, placebo-controlled trial. Circulation 70:1012–1017 (1984).
H. K. Gold, R. C. Leinbach, H. D. Garabedian, T. Yasuda, J. A. Johns, E. B. Grossbard, I. Palacios, and D. Collen. Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: Prevention by maintenance infusion. Circulation 73:347–352 (1986).
TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. N. Engl. J. Med. 312:932–936 (1985).
M. Verstraete, M. Bory, D. Collen, R. Erbel, R. J. Lennane, D. Mathey, H. R. Michels, M. Schartl, R. Uebis, R. Bernard, R. W. Brower, D. P. deBobo, W. Huhmann, J. Lubsen, J. Meyer, W. Rutsch, W. Schmidt, and R. von Essen. Randomized trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Report from the European Cooperative Study Group for Recombinant Tissue-Type Plasminogen Activator. Lancet 2:842–847 (1985).
D. V. Goeddel, W. J. Kohr, D. Pennica, and G. A. Vehar. Human tissue-type plasminogen activator, pharmaceutical compositions containing it, process for making it, and DNA and transformed cell intermediates therefore, U.K. Patent, 2119804, 1983.
M. W. Spellman, C. K. Ferguson, and J. V. O'Connor. Characterization of N-linked oligosaccharides from recombinant tissue-type plasminogen activator. XIIIth International Carbohydrate Symposium, Ithaca, NY, 1986.
D. Pennica, W. E. Holmes, W. J. Kohr, R. N. Harkins, G. A. Vehar, C. A. Ward, W. F. Bennett, E. Yelverton, P. H. Seeburg, H. L. Heyneker, D. V. Goeddel, and D. Collen. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 301:214–221 (1983).
P. Wallen, G. Pohl, N. Bergsdorf, M. Rånby, T. Ny, and H. Jörnvall. Purification and characterization of a melanoma cell plasminogen activator. Eur. J. Biochem. 132:681–686 (1983).
G. A. Vehar, W. J. Kohr, W. F. Bennett, D. Pennica, C. A. Ward, R. Keck, R. N. Harkins, and D. Collen. Characterization studies on human melanoma cell tissue plasminogen activator. Biotechnology 2:1051–1057 (1984).
G. A. Vehar, M. W. Spellman, B. A. Keyt, C. K. Ferguson, R. G. Keck, R. C. Chloupec, R. Harris, W. F. Bennett, S. E. Builder, and W. S. Hancock. Characterization studies on human tissue-type plasminogen activator produced by recombinant DNA technology. Cold Spring Harbor Symp. Quant. Biol., 1986.
C. Bakhit, D. Lewis, V. Busch, P. Tanswell, and M. Mohler. Biodisposition and catabolism of tissue-type plasminogen activator in rats and rabbits. Fibrinolysis 2:31–36 (1988).
M. Einarsson, Smedsrod, and H. Pertoft. Uptake and degradation of tissue plasminogen activator in rat liver. Thromb. Haemostas. 59:474–479 (1988).
C. Bakhit, D. Lewis, R. Billings, and B. Malfroy. Cellular catabolism of recombinant tissue-type plasminogen activator. Identification and characterization of a novel high affinity uptake system on rat hepatocytes. J. Biol. Chem. 262:8716–8720 (1987).
I. Dodd, B. Nunn, and J. H. Robinson. Isolation, identification, and pharmacokinetic properties of human tissue-type plasminogen activator species: Possible localization of a clearance recognition site. Thromb. Haemostas. 59:523–528 (1988).
A. Hotchkiss, C. J. Refino, C. K. Leonard, J. V. O'Connor, C. Crowley, J. McCabe, K. Tate, G. Nakamura, D. Powers, A. Levinson, M. Mohler, and M. W. Spellman. The influence of carbohydrate structure on the clearance of recombinant tissue-type plasminogen activator. Thromb. Haemostas. 60:255–261 (1988).
O. D. Sherwood. Relaxin, In E. Knobil and J. Neill (eds.), The Physiology of Reproduction, Raven Press, New York, 1988, pp. 585–673.
P. D. Johnston, J. Burnier, S. Chen, D. Davis, H. Morehead, M. Remington, M. Struble, G. Tregear, and H. Niall. Structure/function studies on human relaxin. In C. M. Deber, V. J. Hruby, and K. D. Kopple (eds.), Peptides: Structure and Function, Pierce Chemical Co., 1985, pp. 683–686.
P. Tanswell, G. Heinzel, A. Greischel, and J. Krause. Nonlinear pharmacokinetics of tissue-type plasminogen activator in three animal species and isolated perfused rat liver. J. Pharmacol. Exp. Ther. 255:318–324 (1990).
H. Boxenbaum. Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: Extrapolation of data to benzodiazepines and phenytoin. J. Pharmacokinet. Biopharm. 8:165–176 (1980).
J. Mordenti and J. D. Green. The role of pharmacokinetics and pharmacodynamics in the development of therapeutic proteins. In A. Rescigno and A. K. Thakur (eds.), New Trends in Pharmacokinetics, NATO ASI Series, Plenum, New York, 1991, pp. 411–424.
J. O. Kahn, J. D. Allan, T. L. Hodges, L. D. Kaplan, C. J. Arri, H. F. Fitch, A. E. Izu, J. Mordenti, S. A. Sherwin, J. E. Groopman, and P. A. Volberding. The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex: A Phase I study. Ann. Int. Med. 112:254–261 (1990).
E. D. Sprengers and C. Kluft. Plasminogen activator inhibitors. Blood 2:381–387 (1987).
M. A. Hassett, C. Krishnamurti, C. F. Barr, and B. M. Alving. The rabbit as a model for studies of fibrinolysis. Thrombo. Res. 43:313–323 (1986).
G. V. Andreenko and E. E. Shimonaeva. Determination of the antiactivator activity in human and animal blood plasma using tissue plasminogen activator. Vopr. Med. Khim. 29:112–124 (1983).
J. A. Moore, G. Christopher, N. Rudman, J. MacLachlan, G. B. Fuller, B. Burnett, and J. W. Frane. Equivalent potency and pharmacokinetics of recombinant human growth hormones with or without an N-terminal methionine. Endocrinology 122:2920–2926 (1988).
J. Stassen, I. Vanlinthout, H. Lijnen, and D. Collen. A hamster pulmonary embolism model for the evaluation of the thrombolytic and pharmacokinetic properties of thrombolytic agents. Fibronlysis 4 (Suppl. 2):15–21 (1990).
R. A. Baughman. Pharmacokinetics of tissue plasminogen activator. In B. Sobel, D. Collen, and E. Grossbard (eds.), Tissue Plasminogen Activator in Thrombolytic Therapy, Marcel Dekker, New York, 1987, pp. 41–53.
K.-L. Fong, C. S. Crysler, B. A. Mico, K. E. Boyle, G. A. Kopia, L. Kopaciewicz, and R. K. Lynn. Dose-dependent pharmacokinetics of recombinant tissue-type plasminogen activator in anesthetized dogs following intravenous infusion. Drug Metab. Dispos. 16:201–206 (1988).
P. Tanswell, E. Seifried, P. C. A. F. Su, W. Feuerer, and D. C. Rijken. Pharmacokinetics and systemic effects of tissue-type plasminogen activator in normal subjects. Clin. Pharmacol. Ther. 46:155–162 (1989).
K. P. Fu, S. Lee, W. T. Hum, N. Kalyan, R. Rappaport, N. Hetzel, and P. P. Hung. Disposition of a novel recombinant tissue plasminogen activator, delta2-89 tPA, in mice. Thromb. Res. 50:33–41 (1988).
B. L. Ferraiolo, M. Cronin, C. Bakhit, M. Roth, M. Chestnut, and R. Lyon. The pharmacokinetics and pharmacodynamics of a human relaxin in the mouse pubic symphysis bioassay. Endocrinology 125:2922–2926 (1989).
R. Yarchoan, R. V. Thomas, J. M. Pluda, C. F. Perno, H. Mitsuya, K. S. Marczyk, S. A. Sherwin, and S. Broder. Phase I study of the administration of recombinant soluble CD4 (rCD4) by continuous infusion to patients with AIDS or ARC (abstract M.C.P. 137). Proceedings V International Conference on AIDS, Montreal, Canada, 1989.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mordenti, J., Chen, S.A., Moore, J.A. et al. Interspecies Scaling of Clearance and Volume of Distribution Data for Five Therapeutic Proteins. Pharm Res 8, 1351–1359 (1991). https://doi.org/10.1023/A:1015836720294
Issue Date:
DOI: https://doi.org/10.1023/A:1015836720294