Systemic Pharmacokinetic Principles of Therapeutic Peptides

Peptide-based therapeutics represent a rapidly expanding class of drugs. Endogenous peptides typically exhibit short elimination half-lives due to proteolytic cleavage and renal filtration. However, modifications such as amino acid substitutions and fatty-acid conjugation can significantly prolong their half-lives, enabling, for example, once weekly dosing. This study revisits the systemic pharmacokinetics of peptide drugs using classical pharmacokinetic principles and elucidates the scaling of peptide pharmacokinetics across species. Preclinical and clinical pharmacokinetic data were collected from published literature and AstraZeneca internal sources, covering four unconjugated peptides (teduglutide, apraglutide, pramlintide, and exenatide) and five fatty-acid conjugated peptides (tirzepatide, cotadutide, liraglutide, semaglutide and pemvidutide). Algebraic equations for clearance, volume of distribution, and plasma half-life were derived. Theoretical predictions from these models were broadly consistent with collected data; however, there was a tendency to overpredict the volume of distribution. Furthermore, for each peptide drug, these pharmacokinetic parameters were well described by inter-species allometric relationships. The allometric exponents for apparent clearance ranged from 0.58 to 0.88 (geometric mean: 0.72; n = 9; R2 ≥ 0.93), while those for apparent volume of distribution ranged from 0.89 to 1.1 (geometric mean: 0.98; n = 8; R2 ≥ 0.88). Notably, there were no differences in scaling exponents between unconjugated and fatty-acid conjugated peptides. In summary, our results underscore that the systemic pharmacokinetics of peptide drugs generally follow size-related physiological scaling patterns and provide quantitative tools to facilitate translational assessments in the drug discovery process.