What is the half-life of semaglutide (Glucagon-like peptide-1 (GLP-1) receptor agonist)?

Half-Life of Semaglutide

Semaglutide has an elimination half-life of approximately 1 week (7 days), which allows for once-weekly dosing and results in the drug being present in the circulation for about 5 weeks after the last dose. 1

Pharmacokinetic Properties

Semaglutide is a GLP-1 receptor agonist with several key pharmacokinetic characteristics:

• Absorption and Bioavailability:

  • Absolute bioavailability: 89%
  • Maximum concentration reached: 1-3 days post-dose
  • Steady-state exposure: Achieved after 4-5 weeks of once-weekly administration 1

• Distribution:

  • Mean apparent volume of distribution: Approximately 12.5 L
  • Protein binding: Extensively bound to plasma albumin (>99%) 1

• Elimination:

  • Primary route: Metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain
  • Apparent clearance: Approximately 0.05 L/h
  • Elimination half-life: Approximately 1 week 1, 2
  • Presence in circulation: About 5 weeks after the last dose 1

• Excretion:

  • Primary excretion routes: Urine and feces
  • Approximately 3% of the dose is excreted in the urine as intact semaglutide 1

Mechanism of Prolonged Half-Life

The extended half-life of semaglutide is achieved through specific molecular modifications:

• Primary protraction mechanism: Albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid 1
• Additional modifications:
  • Position 8 modification: Provides stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4)
  • Position 34 minor modification: Ensures attachment of only one fatty di-acid 1

These structural modifications result in decreased renal clearance and protection from metabolic degradation, contributing to the long half-life that enables once-weekly dosing.

Clinical Implications of Half-Life

The approximately 1-week half-life of semaglutide has important clinical implications:

• Dosing frequency: Allows for once-weekly administration rather than daily dosing 3
• Steady state: Reached after 4-5 weeks of once-weekly administration 1
• Accumulation: Occurs as expected based on the half-life and dosing interval 4
• Persistence after discontinuation: Semaglutide remains in circulation for approximately 5 weeks after the last dose 1

Potential Pitfalls and Considerations

• Drug discontinuation: Due to the long half-life, effects may persist for several weeks after discontinuation, which is important to consider when managing adverse effects or switching therapies
• Delayed gastric emptying: Semaglutide causes a delay in early postprandial gastric emptying, which may affect the absorption of concomitantly administered oral medications 1, 5
• Adverse effects: If a patient experiences significant adverse effects (particularly gastrointestinal), these may persist longer due to the extended half-life

The long half-life of semaglutide is a key pharmacokinetic feature that provides the clinical advantage of once-weekly dosing but also requires consideration when initiating, adjusting, or discontinuing therapy.