Pharmacokinetics and Pharmacokinetic–Pharmacodynamic Correlations of Therapeutic Peptides

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.

Prolonged Acetaminophen-Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration, and Urinary Adduct Concentrations After Acetaminophen Overdose

“…This is in keeping with animal studies that have isolated protein adducts and found them to generally range from about 50,000 to more than 100,000 Da [14]. Such high molecular weight proteins do not undergo significant glomerular filtration or other forms of renal clearance [15]. Furthermore, 68 % of 557 urine samples contained no quantifiable APAP-CYS, even when serum adduct concentrations were as high as 16.99 μM (Fig.…”

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

“…More recently, we have documented that RERF prevents both uPAR 88-92 -and VEGF-induced angiogenesis in vitro and in vivo (13). However, RERF is expected to have some pharmacokinetic drawbacks as drug candidate, which are common to peptides: they are usually very susceptible to proteolytic degradation in vivo and are rapidly cleared from the circulation in minutes (36). To overcome these drawbacks, we have generated a series of peptide analogues of RERF containing Ca-methyl-a-amino acids, a structural modification used in the past to overcome these limitations (37).…”

Exploitation of the Ornithine Effect Enhances Characterization of Stapled and Cyclic Peptides

“…C yclic, stapled, and branched peptides constitute a unique and growing class of biomolecules with promise as therapeutics because of their biostability and resistance to proteolytic digestion in physiological environments [1][2][3][4][5][6][7]. In the context of therapeutics, peptide-based drug candidates display both advantages and disadvantages in comparison to their small molecule counterparts.…”

“…Peptides, while frequently less toxic than small molecules when administered intravenously and exhibiting higher selectivity for specific biological functions, do not traverse cell membranes with the ease that small molecules do and are prone to proteolytic degradation [8,9]. However, peptides that are protected from degradation via cyclization or stapling have been shown to exhibit high potency and low toxicity, resulting in more promising candidates for drug administration than their linear counterparts [3][4][5][6][7]. A myriad of nonlinear peptides are found naturally in plants, fungi, and bacteria as well as synthetic ones produced in the laboratory [10][11][12][13][14][15][16][17][18].…”