Half-Life
The time required for the concentration of a drug in the body to decrease by half. Half-life determines how frequently a drug must be administered. Natural GLP-1 has a half-life of 1-2 minutes, while semaglutide's modifications extend its half-life to approximately one week, enabling weekly dosing.
Technical Context
Half-life (t1/2) is related to clearance (CL) and volume of distribution (Vd) by the equation: t1/2 = 0.693 × Vd/CL. Native GLP-1: t1/2 ≈ 1-2 min (rapid DPP-4 cleavage). Exenatide: t1/2 ≈ 2.4 hours (DPP-4 resistant exendin-4 backbone, twice-daily dosing). Liraglutide: t1/2 ≈ 13 hours (C-16 albumin binding, daily dosing). Semaglutide SC: t1/2 ≈ 165 hours ≈ 1 week (C-18 albumin binding + Aib, weekly dosing). Half-life extension strategies for peptides include: albumin binding (lipidation), PEGylation (increased size), Fc fusion (FcRn recycling — used by dulaglutide and romiplostim), depot formulations (microspheres, implants), and amino acid modifications (DPP-4 resistance, protease resistance). Achieving the desired half-life is a primary goal of peptide drug design.