Antibodies pp 249-273 | Cite as

The Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies

Preclinical and clinical safety evaluations
  • David B. Haughey
  • Paula M. Jardieu


The genetic engineering of an immunoglobulin construct with the variable region of a mouse monoclonal antibody (mAb) and the constant region of a human immunoglobulin has resulted in the development and production of chimeric mouse/human mAbs with improved biologic activity, long residence times and reduced immunogenicity (Morrison et al., 1984, Morrison, 1985). In an attempt to further reduce immunogenicity, recombinant DNA technology has been used to generate “humanized” mAbs with mouse sequences largely confined to the hypervariable regions.


Allometric Scaling Lysosomal Degradation Human Intestinal Epithelial Cell Major Histocompatability Complex Class Preclinical Toxicology Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adolph, E.F., 1949, Quantitative relations in the physiological constitutions of mammals. Science, 109:579–585PubMedCrossRefGoogle Scholar
  2. Anonomous, 1994, Dose-response information to support drug registration. Federal Register 59:55972–55976Google Scholar
  3. Anonomous, 1997, Points to consider in the manufacture and testing of monoclonal antibody Products for human use. FDA Center for Biologics Evaluation and Research Document, 94D-0259, Rockville, MDGoogle Scholar
  4. Aurrand-Lions, M., Johnson-Leger, C., Wong, C., Du Pasquier, L., and Imhof, B.A., 2001, Heterogeneity of endothelial junctions is reflected by differential expression and specific subcellular localization of three JAM family members. Blood, 98:3699–3707PubMedCrossRefGoogle Scholar
  5. Baert, F., Noman, M., Vermeire, S., Van Assche, G. V., D’Haens, G., Carbonez, A., and Rutgeerts, P., 2003, Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N. Eng. J. Med, 348:601–608CrossRefGoogle Scholar
  6. Berryman, M. and Rodewald, R., 1995, Beta-2-microglobulin co-distributes with the heavy chain of the intestinal IgG-Fc receptor throughout the transepithelial transport pathway of the neonatal rat. J. Cell Sci, 108:2347–2360PubMedGoogle Scholar
  7. Bauer, R.J., Dedrick, R.L., White, M.L., Murray, M.J., and Garovoy, M.R., 1999, Population pharmacokinetics and pharmacodynamics of the anti-CD 11a antibody hull24 in human subjects with psoriasis. J. Pharmacokinet. Biopharm., 27:397–420PubMedGoogle Scholar
  8. Bauer, J.A. and Fung, H.L., 1994, Pharmacodynamic models of nitroglycerin-induced hemodynamic tolerance in experimental heart failure. Pharm. Res. 11:816–823PubMedCrossRefGoogle Scholar
  9. Baxter, L.T., Zhu H., Mackensen, D.G., Butler, W.F., and Jain, R.K., 1995, Biodistribution of monoclonal antibodies: sacle-up from mouse to human using a physiologically based pharmacokinetic model. Cancer Res., 55:4611–4622PubMedGoogle Scholar
  10. Benincosa, L.J., Chow, F-S., Tobia, L.P., Kwok, D.C., Davis, C.B., and Jusko, W.J., 2000, Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys. J. Pharmacol. Exp. Ther., 292:810–816PubMedGoogle Scholar
  11. Bischoff, K.B., Dedrick, R.L., Zaharko, D.S., and Longstreth, J.A., 1971, Methotrexate pharmacokinetics. J. Pharm. Sci., 60:1128–1133PubMedCrossRefGoogle Scholar
  12. Brambell, F.W., 1966, The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet, 2:1087–93PubMedCrossRefGoogle Scholar
  13. Chow, F-S., Benincosa, L.J., Sheth, S.B., Wilson, D., Davis, C.B., Minthorn, E.A. and Jusko, W.J., 2002, Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans. J. Pharmacol. Ther., 71:235–245Google Scholar
  14. Colburn, W.A., 1997, Selecting and validating biologic markers for drug development. J. Clin. Pharmacol., 37:355–362PubMedGoogle Scholar
  15. Damle, B., Tay, L., Comereski, C., Warner, W., and Kaul, S., 2000, Influence of immunogenicity on the pharmacokinetics of BMS-191352, a Pseudomonas exotoxin immunoconjugate, in rats and dogs. J. Pharm. Pharmacol., 52:671–678PubMedCrossRefGoogle Scholar
  16. Davis, C.B., Hepburn, T.W., Urbanski, J.J., Kwok, D.C., Hart, T.K., Herzyk, DJ., Demuth, S.G., Leland, M., and Rhodes, G.R., 1995, Preclinical pharmacokinetic evaluation of the respiratory syncytial virus-specific reshaped human monoclonal antibody RSHZ19. Drug Metab. Dispo., 23:1028–1036Google Scholar
  17. Davis, C.B., Garver, E.M., Kwok, D.C., and Urbanski, J.J., 1996, Disposition of metabolically radiolabeled CE9.1-a macaque-human chimeric anti-human CD4 monoclonal antibody-in transgenic mice bearing human CD4. Drug Metab. Dispo., 24:1032–1037Google Scholar
  18. Dayneka, N., Garg, V., and Jusko, V., 1993, Comparison of four basic models of indirect pharmacodynamic responses. J. Pharmacokinet. Biopharm., 21:457–478PubMedGoogle Scholar
  19. DeHaas, M., 2001, IgG-Fc receptors and the clinical relevance of their polymorphisms. Wien. Klin. Wochenschr, 113:825–31Google Scholar
  20. Dedrick, R.L. and Bischoff, K.B., 1980, Species similarities in pharmacokinetics. Fed. Proc, 39:54–59PubMedGoogle Scholar
  21. Derendorf, H. and Meibohm, B., 1999, Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives. Pharm. Res., 16:176–185PubMedCrossRefGoogle Scholar
  22. Derendorf H., Lesko, L.J., Chaikin, P., Colburn, W.A., Lee, P., Miller, R., Powell, R., Rhodes, G., Stanski, D., Venitz, J., 2000, Pharmacokinetic/pharmacodynamic modeling in drug research and development. J. Clin. Pharmacol., 40:1399–1418PubMedGoogle Scholar
  23. Dickinson, B.L., Badizadegan, K., Wu, Z., Ahouse, J.C., Zhu, X., Simister, N.E., Blumberg, R.S., and Lencer, W.I., 1999, Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. J. Clin. Invest., 104:903–911PubMedCrossRefGoogle Scholar
  24. Eger, R.R., Covell, D.G., Carrasquillo, J.A., Abrams, P.G., Foon, K.A., Reynolds, J.C., Schroff, R.W., Morgan, A.C., Larson, S.M., and Weinstein, J.N., 1987, Kinetic model for the biodistribution of an 111in-labeled monoclonal antibody in humans. Cancer Res., 47:3328–3336PubMedGoogle Scholar
  25. Everitt, D.E., Davis, C.B., Thompson, K., DiCicco, R., Ilson, B., Demuth, S.G., Herzyk, D.J., and Jorkasky, D.K., 1996, The pharmacokinetics, antigenicity, and fusion-inhibition activity of RSHZ19, a humanized monoclonal antibody to respiratory syncytial virus, in healthy volunteers. J. Infect. Dis., 174:463–469PubMedCrossRefGoogle Scholar
  26. Fishwild, D.M., Hudson, D.V., Deshpande U., Kung, A.H., 1999, Differential effects of administration of a human anti-CD4 monoclonal antibody, HMG6, in nonhuman primates. Clin. Immunol. 92:138–152PubMedCrossRefGoogle Scholar
  27. Foster, P.S., Hogan, S.P., Yang, M, Mattes, J., Young, I.G., Matthaei, K.I., Kumar, R.K., Mahalingam, S., and Webb, D.C., 2002, Interleukin-5 and eosinophils as therapeutic agents for asthma. Trends. Mol. Sci., 8:162–167CrossRefGoogle Scholar
  28. Fox, J.A., Hotaling, T.E., Struble, C., Ruppel, J., Bates, D.J., and Schoenhoff, M.B., 1996, Tissue distribution and comples formation with IgE of and anti-IgE antibody after intravenous administration in cynomolgus monkeys. J. Pharmacol. Exp. Ther, 279:1000–1008PubMedGoogle Scholar
  29. Froelich, J., Schoenhoff, M., Tremblay, T., Ruppel, B.A., and Jardieu, P., 1995, Initial human study with a humanized recombinant anti-IgE monoclonal antibody: safety, tolerance and pharmacokinetic (PK)/Dynamic profile. Clin. Pharmacol. Ther., 67:162Google Scholar
  30. Gabrielsson, J., Jusko, W.J., and Alari, L., 2000, Modeling of dose-response-time data: four examples of estimating the turnover parameters and generating kinetic functions from response profiles. Biopharm. Drug Dispos., 21:41–52PubMedCrossRefGoogle Scholar
  31. Ghetie, V. and Ward, E.S., 2000, Multiple roles for the major histocompatability complex class I-related receptor FcRn. Ann. Rev. Immunol, 18:739–766CrossRefGoogle Scholar
  32. Gibaldi, M. and Perrier, D., 1975, Pharmacokinetics. In Drugs and the Pharmaceutical Sciences (J. Swarbrick, ed.), Marcel Dekker, New York, pp. 55–59Google Scholar
  33. Gibaldi, M. and Perrier, D., 1982, Pharmacokinetics. In Drugs and the Pharmaceutical Sciences (J. Swarbrick, ed.), Marcel Dekker, New York, pp. 221Google Scholar
  34. Gobburu, J.V.S., Tenhoor, C., Rogge, M.C., Frazier, D.E., Thomas, D., Benjamin, C., Hess, D.M., and Jusko, W.J., 1998, Pharmacokinetics/dynamics of 5c8, a monoclonal antibody to CD 154 (CD40 ligand) suppression of an immune response in monkeys. J. Pharmacol. Exp. Ther., 286:925–930PubMedGoogle Scholar
  35. Gobburu, J.V.S., Agerso, H., Jusko, W.J., and Ynddal, L., 1999, Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers., Pharm. Res., 16:1412–1416PubMedCrossRefGoogle Scholar
  36. Harrison, P.T., Davis, W., Norman, J.C., Hockaday, A.R., and Allen, J.M., 1994, Binding of monomeric immunoglobulin G triggers FcyRI-mediated endocytosis. J. Biol. Chem., 269:24396–24402PubMedGoogle Scholar
  37. Holford, N.H.G. and Sheiner, L.B., 1982, Kinetics of pharmacological response. Pharmacol. Ther. 16:143–166PubMedCrossRefGoogle Scholar
  38. Israel, E.J., Taylor, S., Wu, Z., Mizoguchi, E., Blumberg, R.S., Bhan, A., and Simister, N.E., 1997, Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology, 92:69–74PubMedCrossRefGoogle Scholar
  39. Khazaeli, M.B., Saleh, M.N., Liu, T.P., Meredith, R.F., Wheeler, R.H., Baker, T.S., King, D., Sécher, D., Allen, L., Rogers, K., Colcher, D., Schlom, J., Shochat, D., and LoBuglio, A.F., 1991, Pharmacokinetics and immune response of 131I-chimeric mouse/human B72.3 (human γ4) monoclonal antibody in humans. Cancer Res., 51:5461–5466PubMedGoogle Scholar
  40. Klingbeil, C. and Hsu, D., 1999, Pharmacology and safety assessment of humanized monoclonal antibodies for therapeutic use. Toxicol. Path., 27:1–3CrossRefGoogle Scholar
  41. Leckie, M.J., ten Brinke, A., Khan, J., Diamant, Z., O’Connor, B.J., Walls, CM., Mathur, A.K., Cowley, H.C, Chung, K.F., Djukanovic, R., Hansel, T.T., Holgate, T., Sterk, P.J. and Barnes, P.J. Lancet, 356:2144–2148Google Scholar
  42. Levy, G., 1986, Kinetics of drug action: an overview. J. Allergy Clin. Immunol., 78:754–761PubMedCrossRefGoogle Scholar
  43. Lin, Y.S., Nguyen, C., Mendoza, J-L., Escandon, E., Fei, D., Meng, Y.G., and Modi, N.B., 1999, Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor. J. Pharmacol. Exp. Ther., 288: 371–378PubMedGoogle Scholar
  44. Mager, D.E. and Jusko, W.J., 2002, Receptor-mediated Pharmacokinetic/pharmacodynamic model of interferon-ß 1a in humans. Pharm. Res., 19:1537–1543PubMedCrossRefGoogle Scholar
  45. Marsh, M. and Helenius, A., 1980, Adsorptive endocytosis of Semliki Forest virus. J. Mol. Biol., 142:439–454PubMedCrossRefGoogle Scholar
  46. Mason, U., Aldrich, J., Breedveld, F., Davis, C.B., Elliott, M., Jackson, M., Jorgensen, C, Keystone, E., Levy, R., Tesser, J., Totoritis, M., Truneh, A., Weisman, M., Wiesenhutter, C, Yocum, D., and Zhu, J., 2002, CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J. Rheumatol, 29:220–229PubMedGoogle Scholar
  47. Meijer, R.T., Koopmans, R.P., Ten Berg, I.J.M., and Schellekens, P.T.A, 2002, Pharmacokinetics of murine anti-human CD3 antibodies in man are determined by the disappearance of target antigen. J. Pharmacol. Exp. Ther., 300:346–353PubMedCrossRefGoogle Scholar
  48. Mordenti, J., 1986, Man versus beast:pharmacokinetic scaling in mammals. J. Pharm. Sci., 75:1028–1040PubMedCrossRefGoogle Scholar
  49. Mordenti, J., Thomsen, K., Licko, V., Chen, H., Meng, Y.G., and Ferrara, N., 1999, Efficacy and concentration-responseof murine anti-VEGF monoclonal antibody in tumour-bearing mice and extrapolation to humans. Toxicol. Pathol, 27:14–21.PubMedCrossRefGoogle Scholar
  50. Mordenti, J., Chen, S.A., Moore, J.A., Ferraiolo, B.L., and Green, J.D., 1991, Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm. Res., 8:1351–1359PubMedCrossRefGoogle Scholar
  51. Morell, A., Terry, W.D., and Waldmann, T.A., 1970, Metabolic properties og IgG subclasses in man. J. Clin. Investig., 49:673–680PubMedCrossRefGoogle Scholar
  52. Morrison, S.L., Johnson, M.J., Herzenberg, L.A., and Oi, V.T., 1984, Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl. Acad. Sci. 81:6851–6855PubMedCrossRefGoogle Scholar
  53. Morrison, S.L., 1985, Transfectomas provide novel chimeric antibodies. Science. 229:1202–1207PubMedCrossRefGoogle Scholar
  54. Mould, D.R., Davis, C.B., Minthorn, E.A., Kwok, D.C., Elliott M.J., Luggen, M.E., and Totoritis, M.C., 1999, A population pharmacokinetic-pharmacodynamic analysis of single doses of clenoliximab in patients with rheumatoid arthritis. Clin. Pharmacol. Ther., 66:246–257PubMedCrossRefGoogle Scholar
  55. Nagashima, R., O’Reilly, R.A., Levy, G., 1969, Kinetics of pharmacologie effects in man: the anticoagulant action of warfarin. Clin. Pharmacol. Then, 10:22–35Google Scholar
  56. Ober, R.J., Radu, CG, Ghetie, V., and Ward, E.S., 2001, Differences in promiscuity for antibody-FcRn interactions across-species: implications for therapeutic antibodies. Int. Immunol, 13:1551–1559PubMedCrossRefGoogle Scholar
  57. Ryan, A.M., Eppler, D.B., Hagler, K.E., Bruner, R.H., Thomford, P.G., Hall, R.L., Shopp, G.M., O’Neill, CA., 1999, Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol. Pathol., 27:78–86PubMedCrossRefGoogle Scholar
  58. Sharma, A., Davis, C.B., Tobia, L.A., Kwok, D.C., Tucci, M.G., Gore, E.R., Herzyk, D.A., and Hart, T.K., 2000, Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4. J. Pharmacol. Exp. Ther., 293:33–41PubMedGoogle Scholar
  59. Sheiner, L.B., Stanski, D.R., Vozeh, R.D., Miller, R.D., Ham, J., 1979,Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin. Pharmacol. Ther, 25:358–371PubMedGoogle Scholar
  60. Simister, N.E., 1989, An Fc receptor structurally related to MHC class I antigens. Nature, 337:184–187PubMedCrossRefGoogle Scholar
  61. Supersaxo, A., Hein, W., and Steffen, H., 1990, Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm. Res., 7:167–169PubMedCrossRefGoogle Scholar
  62. Tanswell, P., Garin-Chesa, P., Rettig, W.J., Welt, S., Divgi, C.R., Casper, E.S., Finn, R.D., Larson, S.M., Old, L.J., and Scott, A.M., 2001, Population pharmacokinetics of antifibroblast activation protein monoclonal antibody in cancer patients. Br. J. Clin. Pharmacol, 51:177–180PubMedCrossRefGoogle Scholar
  63. Trang, J.M., LoBuglio,A.F., Wheeler, R.H., Harvey, E.B., Sun, L., Ghrayeb, J., and Khazaeli, M.B., 1990, Pharmacokinetics of a mouse/human chimeric monoclonal antibody (C-17-1A) in metastatic adenocarcinoma patients. Pharm. Res., 7:587–592PubMedCrossRefGoogle Scholar
  64. Ward, E.S., Zhou, J., Ghetie, V., and Ober, R.J., 2003, Evidence to support the cellular mechanism involved in serum IgG homeostatis in humans. Int. Immunol., 15:187–195PubMedCrossRefGoogle Scholar
  65. Weiss, M., Sziegoleit, W., and Forster, W., 1977, Dependence of pharmacokinetic parameters on body weight. Int. J. Clin. Pharmacol., 15:572–575Google Scholar
  66. Xu, Z.X., Sun, Y.N., DuBois, D.C., Almon, R.R., and Jusko, W.J. Third-generation model for corticosteroid pharmacodynamics: Roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver. J. Pharmacokinet. Biopharm., 23:163–181Google Scholar
  67. Zaharko, D.S., Dedrick, R.L., and Oliverio, V.T., 1972, Prediction of the distribution of methotrexate in the sting rays Dasyatidae Sabrina and sayi by use of a model developed in mice. Comp. Biohem. PhysiolA., 42:183–194CrossRefGoogle Scholar
  68. Zia-Amirhosseini, P., Minthorn, E., Benincosa, L.J., Hart, T.K., Hottenstein, C.S., Tobia, L.A.P, and Davis, C.B., 1999, Pharmacokinetics and pharmacodynamics of SB-2404653, a humanized monoclonal antibody directed to human interleukin-5, in monkeys. J. Pharmacol. Exp. Ther., 291:1060–1067.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • David B. Haughey
    • 1
  • Paula M. Jardieu
    • 1
  1. 1.Prevalere Life Sciences, Inc.Whitesboro

Personalised recommendations