Prediction of Half-Life Extension of Peptides via Serum Albumin Binding: Current Challenges.

Abstract

The development of peptide therapeutics has increased enormously in recent decades. Many of the peptide drugs and antibody fragments that lack Fc backbone have a short half-life in circulation. In general, the half-life supports the design of the dosing regimen and frequency of administration, which are key aspects in the discovery of peptide drugs intended for long duration of action. Less frequent administration such as weekly or monthly can improve compliance and adherence to therapy. Serum albumin binding is a key approach to extend the half-life of peptide drugs. Despite the evidence of half-life prolongation of a variety of peptide drugs via albumin, quantitative prediction for humans is still a key question. Challenges in the measurement ofalbumin binding and in understanding the clearance mechanisms can limit quantitative prediction. We integrated pharmacokinetic concepts and albumin binding across species in a quantitative model to be used as a tool for prediction of half-life. Preliminary validation on a limited dataset indicated a good correlation between predicted and observed values. Further development of more quantitative models is warranted.