Introduction <p>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.</p> Methods <p>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.</p> Results <p>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; <i>n</i> = 9; <i>R</i>² ≥ 0.93), while those for apparent volume of distribution ranged from 0.89 to 1.1 (geometric mean: 0.98; <i>n</i> = 8; <i>R</i>² ≥ 0.88). Notably, there were no differences in scaling exponents between unconjugated and fatty-acid conjugated peptides.</p> Conclusion <p>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.</p>