The pharmacokinetics and pharmacodynamics of monoclonal antibodies – mechanistic modeling applied to drug development

Projections Research Inc, 535 Springview Lane, Phoenixville, PA 19460, USA.
Current opinion in drug discovery & development (Impact Factor: 5.12). 02/2007; 10(1):84-96.
Source: PubMed


The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the structure of the antibody and the physiological system that it targets. Patient exposure and responses to mAbs are also related to the structure and activity of mAbs. Furthermore, the pharmacokinetics and pharmacodynamics of mAbs are often inter-related. Pharmacokinetic and pharmacodynamic modeling have been used to elucidate or support the mechanisms of antibodies in development and can be used to identify appropriate dose regimens. Consequently, pharmacokinetic and pharmacodynamic modeling often plays a larger role during the development of therapeutic mAbs than for small molecules.

Full-text preview

Available from:
  • Source
    • "With a low volume of distribution of 2.5 L/kg, daclizumab probably remains in the plasma compartment for a significant amount of time [67]. It has a molecular weight of 144 kD and has somewhat limited potential to pass into breast milk [68]. Because it is unknown if daclizumab enters breast milk, this drug should be avoided pending further investigation. "
    [Show abstract] [Hide abstract] ABSTRACT: Multiple Sclerosis (MS) is an autoimmune neurological disease characterized by inflammation of the brain and spinal cord. Relapsing-Remitting MS is characterized by acute attacks followed by remission. Treatment is aimed at halting these attacks; therapy may last for months to years. Because MS disproportionately affects females and commonly begins during the childbearing years, clinicians treat pregnant or nursing MS patients. The intent of this review is to perform an in-depth analysis into the safety of drugs used in breastfeeding women with MS. This paper is composed of several drugs used in the treatment of MS and current research regarding their safety in breastfeeding including immunomodulators, immunosuppressants, monoclonal antibodies, corticosteroids, and drugs used for symptomatic treatment. Typically, some medications are large polar molecules which often do not pass into the milk in clinically relevant amounts. For this reason, interferon beta is likely safe for the infant when given to a breastfeeding mother. However, other drugs with particularly dangerous side effects may not be recommended. While treatment options are available and some data from clinical studies does exist, there continues to be a need for investigation and ongoing review of the medications used in breastfeeding mothers.
    Full-text · Article · Feb 2016
    • "Because only IgGs are produced for therapeutic purposes through genetic engineering, the terms recombinant mAb and IgG are often used interchangeably. IgGs are large tetrameric glycoproteins measuring approximately 150 kDa that are structurally composed of four polypeptide chains: two identical heavy chains (HC, ∼50 kDa) and two identical light chains (LC, ∼25 kDa) connected through several inter-and intra-chain disulfide bonds at their hinge region [64]. Each chain is composed of structural domains according to their size and function, giving the constant, variable, and hypervariable regions. "
    [Show abstract] [Hide abstract] ABSTRACT: Ion-exchange chromatography (IEX) is a historical technique widely used for the detailed characterization of therapeutic proteins and can be considered as a reference and powerful technique for the qualitative and quantitative evaluation of charge heterogeneity. The goal of this review is to provide an overview of theoretical and practical aspects of modern IEX applied for the characterization of therapeutic proteins including monoclonal antibodies (Mabs) and antibody drug conjugates (ADCs). The section on method development describes how to select a suitable stationary phase chemistry and dimensions, the mobile phase conditions (pH, nature and concentration of salt), as well as the temperature and flow rate, considering proteins isoelectric point (pI). In addition, both salt-gradient and pH-gradient approaches were critically reviewed and benefits as well as limitations of these two strategies were provided. Finally, several applications, mostly from pharmaceutical industries, illustrate the potential of IEX for the characterization of charge variants of various types of biopharmaceutical products. Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · Feb 2015 · Journal of pharmaceutical and biomedical analysis
  • Source
    • "Although a rather low number of all antibodies developed make it to a worldwide use in clinics, more than 20 antibodies are currently approved by the US Food and Drug Administration [5] . A variety of engineered monoclonal antibodies (mAb) and antibody fragments for difference targets of interest is currently under preclinical inves- tigation678 . Immuno-PET, which is tracking and quantifying of mAbs with PET, can be of great value in several stages of mAb development and application [9]. "
    [Show abstract] [Hide abstract] ABSTRACT: Fast progressing immuno- PET asks to explore new radionuclides. One of the promising candidates is Nb-90. It has a half-life of 14.6 h that allows visualizing and quantifying biological processes with medium and slow kinetics, such as tumor accumulation of antibodies and antibodies fragments or drug delivery systems and nanoparticles. Nb-90 exhibits a positron branching of 53% and an average kinetic energy of emitted positrons of.. mean = 0.35MeV. Currently, radionuclide production routes and Nb V labeling techniques are explored to turn this radionuclide into a useful imaging probe. However, efficient separation of Nb-90 from irradiated targets remains in challenge. Ion exchange based separation of Nb-90 from zirconium targets was investigated in systems AG 1 x 8 - HCl/H2O2 and UTEVA-HCl. Nb-95 (t(1/2) = 35.0 d), Zr-95 (t(1/2) = 64.0 d) and (92m) Nb (t(1/2) = 10.15 d) were chosen for studies on distribution coefficients. Separation after AG 1 x 8 anion exchange yields 99% of Nb-90/95. Subsequent use of a solid-phase extraction step on UTEVA resin further decontaminates Nb-90/95 from traces of zirconium with yields 95% of Nb-90/95. A semi-automated separation takes one hour to obtain an overall recovery of Nb-90/95 of 90%. The amount of Zr was reduced by factor of 10(8). The selected separation provides rapid preparation (< 1h) of high purity Nb-90 appropriate for the synthesis of Nb-90-radiopharmaceuticals, relevant for purposes of immuno-PET. Applying the radioniobium obtained, Nb-90/95-labeling of a monoclonal antibody (rituximab) modified with desferrioxamine achieved labeling yields of> 90% after 1 h incubation at room temperature.
    Full-text · Article · May 2014 · Radiochimica Acta
Show more