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Pharmacokinetics and Pharmacokinetic–Pharmacodynamic Correlations of Therapeutic Peptides

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Abstract

Peptides, defined as polymers of less than 50 amino acids with a molecular weight of less than 10 kDa, represent a fast-growing class of new therapeutics which has unique pharmacokinetic characteristics compared to large proteins or small molecule drugs. Unmodified peptides usually undergo extensive proteolytic cleavage, resulting in short plasma half-lives. As a result of their low permeability and susceptibility to catabolic degradation, therapeutic peptides usually have very limited oral bioavailability and are administered either by the intravenous, subcutaneous, or intramuscular route, although other routes such as nasal delivery are utilized as well. Distribution processes are mainly driven by a combination of diffusion and to a lesser degree convective extravasation dependent on the size of the peptide, with volumes of distribution frequently not larger than the volume of the extracellular body fluid. Owing to the ubiquitous availability of proteases and peptidases throughout the body, proteolytic degradation is not limited to classic elimination organs. Since peptides are generally freely filtered by the kidneys, glomerular filtration and subsequent renal metabolism by proteolysis contribute to the elimination of many therapeutic peptides. Although small peptides have usually limited immunogenicity, formation of anti-drug antibodies with subsequent hypersensitivity reactions has been described for some peptide therapeutics. Numerous strategies have been applied to improve the pharmacokinetic properties of therapeutic peptides, especially to overcome their metabolic instability, low permeability, and limited tissue residence time. Applied techniques include amino acid substitutions, modification of the peptide terminus, inclusion of disulfide bonds, and conjugation with polymers or macromolecules such as antibody fragments or albumin. Application of model-based pharmacokinetic–pharmacodynamic correlations has been widely used for therapeutic peptides in support of drug development and dosage regimen design, especially because their targets are often well-described endogenous regulatory pathways and processes.

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No sources of funding have been used to facilitate the development of this manuscript. Lei Diao and Bernd Meibohm have no potential conflict of interest directly relevant to the content of this review.

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  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Rm. 444, Memphis, TN, 38163, USA

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Diao, L., Meibohm, B. Pharmacokinetics and Pharmacokinetic–Pharmacodynamic Correlations of Therapeutic Peptides. Clin Pharmacokinet 52, 855–868 (2013). https://doi.org/10.1007/s40262-013-0079-0

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