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Pharmacokinetic and Pharmacodynamic Considerations in the Development of Therapeutic Proteins

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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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Acknowledgements

The views expressed in this article are those of the authors and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred. No sources of funding were used to assist in the preparation of this review.

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  1. Clinical Pharmacology and Toxicology Branch, Office of Drug Evaluation VI, Center for Drug Evaluation and Research, Food and Drug Administration, Woodmont Office Center II, 1451 Rockville Pike, Rockville, Maryland, 20852, USA

    Iftekhar Mahmood & Martin D. Green

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Mahmood, I., Green, M.D. Pharmacokinetic and Pharmacodynamic Considerations in the Development of Therapeutic Proteins. Clin Pharmacokinet 44, 331–347 (2005). https://doi.org/10.2165/00003088-200544040-00001

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