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.
What I am after is which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.
If the honest answer is that nobody knows, that is a useful answer and I would rather have it.
Dr.PulmRoch 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…
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.
SarahChen_PharmD said:Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%),…
No disagreement with SarahChen_PharmD. One condition attached. The mechanism is more central than most summaries suggest. Receptor agonism in the arcuate nucleus activates POMC neurons and inhibits AgRP/NPY signalling, and the downstream MC4R pathway is the same one disrupted in monogenic obesity — convergent genetic evidence that the target is the right one. Peripherally there is glucose-dependent insulin secretion, glucagon suppression and delayed gastric emptying, but the gastric component largely adapts over months while the central effect persists, which is why the durable effect is appetite rather than fullness.
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View ResultsDr.PulmRoch 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…
This matches mine closely enough to be worth saying so out loud. Nothing to add that would improve it.
From the other side of the consultation, briefly.
Pharmacist here. I want to add the drug interaction perspective on the pharmacology.
Key points from a pharmacokinetic standpoint:
- GLP-1 agonists delay gastric emptying, which can affect Tmax of co-administered oral medications
- Monitor patients on warfarin (INR), levothyroxine (TSH), and oral contraceptives during dose titration
- The albumin-binding mechanism of semaglutide (C-18 fatty acid linker) gives it the ~168-hour half-life that enables weekly dosing
- Steady state is reached at approximately 4-5 weeks after dose initiation or adjustment
Re: the pharmacology specifically — the pharmacology here is well-characterized and the clinical implications are straightforward.