Duration of Zepbound (Tirzepatide) in the System
Tirzepatide has an elimination half-life of approximately 5 days, meaning it takes about 25 days (5 half-lives) for the medication to be essentially cleared from your system after the last dose. 1
Pharmacokinetic Profile
- The elimination half-life is 5 days, which allows for gradual clearance from the body even with abrupt cessation of therapy 1
- Following subcutaneous administration, tirzepatide is primarily metabolized via proteolytic cleavage of the amino acid backbone, β-oxidation of the C20 diacid moiety, and amide hydrolysis 2
- Renal excretion is the principal route of elimination, with approximately 66% of the administered radioactivity recovered in urine and approximately 33% eliminated in feces in humans 2
Clinical Implications of Drug Clearance
- The parent drug (intact tirzepatide) is the major circulating component in human plasma, with no circulating metabolites representing more than 10% of total drug-related exposure 2
- Intact tirzepatide was not observed in urine or feces, indicating complete metabolism before excretion 2
- Following a single subcutaneous dose, the majority of the excreted dose was recovered within 480 hours (20 days) 2
Physiological Effects After Discontinuation
- Gastric emptying returns toward baseline over days to weeks as the drug clears, though the timeline for complete normalization of gastrointestinal effects varies 1
- Weight regain typically begins within weeks of discontinuation, regardless of how the medication is stopped, with mean weight regain of 6.9% of lost weight over 48 weeks observed in related GLP-1 receptor agonist studies 1
- Metabolic improvements may reverse after discontinuation, requiring reassessment of parameters such as HbA1c (if diabetic), lipids, and blood pressure within 3 months 1
Important Caveats
- The 5-day half-life means that steady-state concentrations are achieved after approximately 4-5 weeks of weekly dosing (4-5 half-lives to reach steady state)
- The medication does not cause physiological dependence requiring gradual dose reduction and does not lead to withdrawal syndromes or rebound effects 1
- Complete pharmacological effects may persist for several weeks after the last dose due to the long half-life and sustained receptor engagement