Cited by 150Biosimilars and Bioanalytical MethodsMonoclonal and Polyclonal Antibodies ResearchProtein purification and stability

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Pharmacokinetic and Pharmacodynamic Considerations in the Development of Therapeutic Proteins

Mahmood, Iftekhar, Green, Martin D·2005·Clinical Pharmacokinetics

DOI 10.2165/00003088-200544040-00001

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Abstract

With an increasing number of therapeutic proteins moving into preclinical and clinical development, pharmacokinetic factors play an important role in the development of these macromolecules. It is also important that the pharmacokinetic evaluation of these compounds be done as accurately as possible. For macromolecules, evaluation of pharmacokinetic parameters is often complicated by a number of factors. Bioanalytical methods are essential for any pharmacokinetic study, but for many therapeutic proteins the immunoassay and bioassay methodologies are often nonspecific and sometimes the estimation of pharmacokinetic parameters becomes assay dependent. In vivo binding proteins, metabolites and antibody formation may also interfere with bioanalytical methodologies and thus may have significant impact on the pharmacokinetics of therapeutic proteins. There are also difficulties in identifying and quantifying metabolites as well as the binding of therapeutic proteins to endogenous proteins. Some macromolecules exhibit species specificity that complicates the preclinical pharmacological and toxicological evaluation of these compounds. Antibody formation is a particular problem in the preclinical evaluation of therapeutic proteins. Changes in structure or sequence of protein molecules (glycosylation or pegylation) may cause changes in the pharmacokinetics of these compounds. The size of therapeutic proteins may become a hindrance for absorption. Low absorption of intact molecules across biological membranes frequently occurs. Other factors that may affect the pharmacokinetics of a therapeutic protein are immunogenicity, presence of endogenous protein, time of drug administration, and rate and site of drug delivery. The relationship between pharmacokinetics and pharmacodynamics of therapeutic proteins is complex and in most cases is unclear. In many cases the mechanism and site of action are unknown for these compounds.

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Type I Interferon Receptor is a Primary Regulator of Target-Mediated Drug Disposition of Interferon-β in Mice
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Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing
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Background
Therapeutic potential of adenovirus-mediated delivery of β-defensin 2 for experimental otitis media
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Glycosylation and antiproliferative activity of hyperglycosylated IFN-α2 potentiate HEK293 cells as biofactories
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Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody
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Clinical Pharmacology Review of Plasma‐derived and Recombinant Protein Products: CBER Experience and Perspectives on Model‐Informed Drug Development
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“Moreover, therapeutic proteins are rapidly eliminated from the body in a short period of time due to enzymatic degradation, leading to temporary therapeutic effects [56].”
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Amphiphilic Cell-Penetrating Peptides Containing Arginine and Hydrophobic Residues as Protein Delivery Agents
Moreno, J., Zoghebi, K. A., Salehi, D., Kim, L., Shoushtari, S. K., Tiwari, R. K., & Parang, K. (2023) · Pharmaceuticals · doi:10.3390/ph16030469 · Cited by 10
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“Additionally, the use of recombinant antigen proteins raises questions, as the interaction between these proteins and the antibodies formed during the immune response can signi ﬁ cantly alter their pharmacodynamics and pharmacokinetics (Mahmood and Green, 2005).”
Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products
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The Molecular Engineering of an Anti-Idiotypic Antibody for Pharmacokinetic Analysis of a Fully Human Anti-Infective
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Optimization of the Near-Infrared Fluorescence Labeling for In Vivo Monitoring of a Protein Drug Distribution in Animal Model
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Pharmacokinetics of antibodies during pregnancy: General pharmacokinetics and pregnancy related physiological changes (Part 1)
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“…affected by adverse local adsorption in subcutaneous administration due to variable protein hydropathy surface, and by rapid elimination from body in intravenous administration, via proteolytic, renal, hepatic, and receptor mediated clearance mechanisms (Mahmood and Green 2005; Tang et al. 2004).”
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Population pharmacokinetics of immunoglobulin intravenous preparation in very low birth weight neonates
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Bispecific Antibodies: Developments and Current Perspectives
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Biopolymer Molecular Weight Can Modulate the Wound Healing Efficacy of Multivalent Sonic Hedgehog–Hyaluronic Acid Conjugates
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Biodistribution, pharmacokinetics and toxicity of a Vasconcellea cundinamarcensis proteinase fraction with pharmacological activity
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More comprehensive standards for monitoring glycosylation.
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Background

Authors: Mahmood, I., & Green, M. D.
Affiliations: United States Food and Drug Administration (US)
Corresponding author: Mahmood, Iftekhar
ORCID: Mahmood, Iftekhar
Venue: Clinical Pharmacokinetics
Publisher: Springer Science and Business Media LLC
Published: 2005
Volume: 44
Issue: 4
Pages: 331-347
ISSN: 0312-5963 (ISSN-L)
DOI: 10.2165/00003088-200544040-00001
OpenAlex: W2038900628
Cited by: 150
References: 82
Citations by year: 2026: 3 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 7 · 2017: 7 · 2016: 7 · 2015: 8 · 2014: 4 · 2013: 12 · 2012: 9
FWCI: 0.48
Type: journal article
Language: en
Open access: closed
Locations: Clinical Pharmacokinetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
Keywords: therapeutic proteins, pharmacokinetics, pharmacodynamics, bioanalytical methods, immunoassay interference, protein binding, metabolite quantification, species specificity, antibody production, immunogenicity, glycosylation, PEGylation, protein absorption, drug delivery, preclinical evaluation
MeSH terms: Absorption, Drug Evaluation, Preclinical, Glycosylation, Humans, Kidney, Liver, Polyethylene Glycols, Proteins, Recombinant Proteins, Drug Delivery Systems

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Pharmacokinetic and Pharmacodynamic Considerations in the Development of Therapeutic Proteins

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