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Antibody Pharmacokinetics and Pharmacodynamics

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Abstract

The U.S. Food and Drug administration (FDA) has approved several polyclonal antibody preparations and at least 18 monoclonal antibody preparations (antibodies, antibody fragments, antibody fusion proteins, etc.). These drugs, which may be considered as a diverse group of therapeutic proteins, are associated with several interesting pharmacokinetic characteristics. Saturable binding with target antigen may influence antibody disposition, potentially leading to nonlinear distribution and elimination. Independent of antigen interaction, concentration‐dependent elimination may be expected for IgG antibodies, due to the influence of the Brambell receptor, FcRn, which protects IgG from catabolism. Antibody administration may induce the development of an endogenous antibody response, which may alter the pharmacokinetics of the therapeutic antibody. Additionally, the pharmacodynamics of antibodies are also complex; these drugs may be used for a wide array of therapeutic applications, and effects may be achieved by a variety of mechanisms. This article provides an overview of many of the complexities associated with antibody pharmacokinetics and pharmacodynamics. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2645–2668, 2004

Section snippets

INTRODUCTION

Interest in the development of antibody drugs is rapidly increasing and, over the last several years, more than 20 antibody products (i.e., antibodies, antibody fragments, or antibody‐fusion proteins) have been approved by the U.S. Food and Drug Administration (FDA) (Tables 1 and 2). Additionally, there is increasing interest in the use of pharmacokinetic and pharmacodynamic analyses to guide and expedite drug development.1 As such, it may be timely and instructive to review the pharmacokinetic

ANTIBODY STRUCTURE

In humans, antibodies may be classified as members of five families (or isotypes), which have been named immune globulin alpha (IgA), delta (IgD), epsilon (IgE), gamma (IgG), and mu (IgM).2 Structural differences between the isotypes, summarized in Table 3, include differences in molecular weight (ranging from ∼150 to ∼1150 kDa) and antigen binding sites (e.g., valence; ranging from 2 to 12). The most prevalent antibody isotype in man is IgG, which comprises approximately 85% of the

Absorption

The majority of FDA‐approved therapeutic antibodies are administered intravenously. The intravenous (iv) route has been preferred because this route of administration allows complete systemic availability, rapid delivery of antibodies to the systemic circulation, and achievement of high concentrations. Additionally, relative to other parenteral routes of administration, the iv route allows the administration of larger volumes. However, iv delivery has its limitations. This route is not

ANTIBODY PHARMACODYNAMICS

Antibodies may act by a wide variety of pathways to achieve a diverse array of pharmacological effects. To facilitate discussion of antibody pharmacodynamics, we have focused our review on four main applications of therapeutic antibodies, where antibodies are used to neutralize toxins (i.e., immunotoxicotherapy), mediate the destruction of cells, alter cellular function, or mediate targeted drug delivery. Each topic area is structured to discuss relevant caveats, cite approved antibody

CONCLUSIONS/SUMMARY

Advances in the field of biotechnology have led to the development of techniques that have enhanced the rate of antibody discovery, reduced the risk of antibody immuno‐toxicity, and increased the feasibility of large‐scale antibody production. As a result of these advances, there has been a dramatic increase in the development of antibodies as drugs, and some investigators have reported that there are more than 700 antibody preparations in clinical trial.136 However, several obstacles have not

Acknowledgements

The authors thank Dr. William Jusko and Dr. Richard Bergstrom for their helpful comments. Supported by grant HL67347 from the National Heart, Lung, and Blood Institute and by grant AI60687 from the National Institute of Allergy and Infectious Diseases.

REFERENCES (147)

  • J.B. Sullivan

    Past, present, and future immunotherapy of snake venom poisoning

    Ann Emerg Med

    (1987)
  • P.R. Pentel et al.

    Drug-specific antibodies as antidotes for tricyclic antidepressant overdose

    Toxicol Lett

    (1995)
  • C. Putterman et al.

    Colchicine intoxication: Clinical pharmacology, risk factors, features, and management

    Semin Arthritis Rheum

    (1991)
  • E.D. Lobo et al.

    Application of pharmacokinetic–pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in mice

    J Pharmaceut Sci

    (2003)
  • J.P. Balthasar et al.

    Inverse targeting of peritoneal tumors: Selective alteration of the disposition of methotrexate through the use of anti-methotrexate antibodies and antibody fragments

    J Pharm Sci

    (1996)
  • K.A. Byrnes-Blake et al.

    Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats

    Eur J Pharmacol

    (2003)
  • G.R. Galluppi et al.

    Integration of pharmacokinetic and pharmacodynamic studies in the discovery, development, and review of protein therapeutic agents: A conference report

    Clin Pharmacol Ther

    (2001)
  • J.K. Frazer et al.

    Immunoglobulins: Structure and function

    Fundamental immunology, 4th edn

    (1999)
  • A. Mountain et al.

    Engineering antibodies for therapy

    Biotechnol Genet Eng Rev

    (1992)
  • C. Klingbeil et al.

    Pharmacology and safety assessment of humanized monoclonal antibodies for therapeutic use

    Toxicol Pathol

    (1999)
  • P.R. Rebello et al.

    Anti-globulin responses to rat and humanized CAMPATH-1 monoclonal antibody used to treat transplant rejection

    Transplantation

    (1999)
  • G.A. Losonsky et al.

    Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis. A pharmacokinetic and functional analysis

    J Clin Invest

    (1985)
  • P.M. Blum et al.

    Survival of oral human immune serum globulin in the gastrointestinal tract of low birth weight infants

    Pediatr Res

    (1981)
  • A. Guarino et al.

    Oral immunoglobulins for treatment of acute rotaviral gastroenteritis

    Pediatrics

    (1994)
  • R.P. Junghans

    Finally! The Brambell receptor (FcRB). Mediator of transmission of immunity and protection from catabolism for IgG

    Immunol Res

    (1997)
  • T.A. Waldmann et al.

    The role of cell-surface receptors in the transport and catabolism of immunoglobulins

    Ciba Found Symp

    (1972)
  • N.E. Simister et al.

    Cloning and expression of the neonatal rat intestinal Fc receptor, a major histocompatibility complex class I antigen homolog

    Cold Spring Harb Symp Quant Biol

    (1989)
  • X. Zhu et al.

    MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells

    J Immunol

    (2001)
  • A. Aarli et al.

    IgG Fc receptors on epithelial cells of distal tubuli and on endothelial cells in human kidney

    Int Arch Allergy Appl Immunol

    (1991)
  • G.M. Spiekermann et al.

    Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: Functional expression of FcRn in the mammalian lung

    J Exp Med

    (2002)
  • P. Zia-Amirhosseini et al.

    Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys

    J Pharmacol Exp Ther

    (1999)
  • C.B. Davis et al.

    Preclinical pharmacokinetic evaluation of the respiratory syncytial virus-specific reshaped human monoclonal antibody RSHZ19

    Drug Metab Dispos

    (1995)
  • J.M. Korth-Bradley et al.

    The pharmacokinetics of etanercept in healthy volunteers

    Ann Pharmacother

    (2000)
  • Y.S. Lin et al.

    Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor

    J Pharmacol Exp Ther

    (1999)
  • S. Pepin et al.

    Snake F(ab')2 antivenom from hyperimmunized horse: Pharmacokinetics following intravenous and intramuscular administrations in rabbits

    Pharm Res

    (1995)
  • M.E. Lebsack et al.

    Absolute bioavailability of TNF receptor fusion protein following subcutaneous injection in healthy volunteers

    Pharmacotherapy

    (1997)
  • A.K. Vaishnaw et al.

    Pharmacokinetics, biologic activity, and tolerability of alefacept by intravenous and intramuscular administration

    J Pharmacokinet Pharmacodyn

    (2002)
  • D.G. Covell et al.

    Pharmacokinetics of monoclonal immunoglobulin G1, F(ab')2, and Fab' in mice

    Cancer Res

    (1986)
  • L.T. Baxter et al.

    Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice

    Cancer Res

    (1994)
  • M.F. Flessner et al.

    In vivo diffusion of immunoglobulin G in muscle: Effects of binding, solute exclusion, and lymphatic removal

    Am J Physiol

    (1997)
  • A. Bill

    Plasma protein dynamics: Albumin and IgG capillary permeability, extravascular movement, and regional blood flow in unanesthetized rabbits

    Acta Physiol Scand

    (1977)
  • M. Juweid et al.

    Accumulation of immunoglobulin G at focal sites of inflammation

    Eur J Nucl Med

    (1992)
  • M.P. Hedger et al.

    Measurement of immunoglobulin G levels in adult rat testicular interstitial fluid and serum

    J Androl

    (1994)
  • B.L. Dickinson et al.

    Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line

    J Clin Invest

    (1999)
  • K.M. McCarthy et al.

    Bidirectional transcytosis of IgG by the rat neonatal Fc receptor expressed in a rat kidney cell line: A system to study protein transport across epithelia

    J Cell Sci

    (2000)
  • M. Gibaldi et al.

    Pharmacokinetics

  • C.F. Molthoff et al.

    Comparison of the pharmacokinetics, biodistribution, and dosimetry of monoclonal antibodies OC125, OV-TL 3, and 139H2 as IgG and F(ab')2 fragments in experimental ovarian cancer

    Br J Cancer

    (1992)
  • K.J. Kairemo et al.

    In vivo detection of intervertebral disk injury using a radiolabeled monoclonal antibody against keratan sulfate

    J Nucl Med

    (2001)
  • S.M. Danilov et al.

    Lung uptake of antibodies to endothelial antigens: Key determinants of vascular immunotargeting

    Am J Physiol Lung Cell Mol Physiol

    (2001)
  • D.L. Delacroix et al.

    Selective transport of polymeric immunoglobulin A in bile. Quantitative relationships of monomeric and polymeric immunoglobulin A, immunoglobulin M, and other proteins in serum, bile, and saliva

    J Clin Invest

    (1982)

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