I went looking for why the dosing schedule is what it is and found that almost every practical question on this board has a pharmacokinetic answer nobody states.
Numbers worth memorising for this class: Tmax one to three days for the weekly peptides, terminal half-life about a week for semaglutide and about five days for tirzepatide, steady state at four to five half-lives, subcutaneous bioavailability high enough that site choice is irrelevant.
So the question, as narrowly as I can put it: which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.
Tell me what I have not thought of.
RunnerRach said:I went looking for why the dosing schedule is what it is and found that almost every practical question on this board has a pharmacokinetic answer…
PK/PD modeling for the pharmacology: understanding the pharmacokinetics helps optimize dosing. Semaglutide:
- Tmax: 24-72 hours post-injection
- T½: ~168 hours (7 days) — enables weekly dosing
- Steady state: reached at 4-5 weeks
- Bioavailability (SubQ): ~89%
- Volume of distribution: ~12.5L (primarily plasma)
The albumin binding (>99%) is the key pharmacological innovation — creating a sustained-release effect from a single injection. Previous GLP-1 agonists (exenatide) required BID dosing due to rapid clearance.
Dr.GastroMayo said:PK/PD modeling for the pharmacology: understanding the pharmacokinetics helps optimize dosing.
Agreeing with Dr.GastroMayo, and the qualification matters more than the agreement. The pharmacokinetics explain nearly every practical question asked here. Albumin binding above 99% slows clearance enough to make weekly dosing possible; a terminal half-life near a week means four to five weeks to steady state and therefore a four-week titration interval; subcutaneous bioavailability around 89% means injection site barely matters. Those three facts answer most timing questions before they are asked.
If somebody has the primary source to hand I would rather cite it than paraphrase it.
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Browse GL BiochemRunnerRach said:I went looking for why the dosing schedule is what it is and found that almost every practical question on this board has a pharmacokinetic answer…
Mine went the same way, slower.
Clinical perspective, offered as context rather than as advice.
Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%), creating a depot effect with a ~168-hour half-life enabling weekly dosing[1].
Tirzepatide is a dual GIP/GLP-1R agonist with higher GIP affinity (5:1 GIP:GLP-1 potency ratio). The GIP component may enhance beta-cell function and adipocyte lipid metabolism beyond what GLP-1 alone achieves.
For the pharmacology, the pharmacology explains the clinical differences between these agents.
[1] Lau J, et al. J Med Chem. 2015;58(18):7370-7380.