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.
The question I want answered is which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.
Practical detail welcome, however dull — the duller the better.
Dr.SleepRoch 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…
Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest trajectory ever seen for an anti-obesity agent[1].
Amylin receptor agonism enhances satiety signaling through the area postrema and reduces glucagon secretion. Combined with GLP-1R agonism, this dual mechanism may produce even greater efficacy than current agents.
Early-stage data — interpret with caution. But the trajectory is extraordinary.
[1] Novo Nordisk investor presentation, September 2023.
amsterdam_pete said:Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest…
That is correct as far as it goes, and here is where it stops going. 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.
Sigma-Aldrich — Research-Grade Standards
Certified reference materials, analytical reagents, and research-grade standards for peptide verification. Trusted by laboratories worldwide.
Shop Reference StandardsDr.SleepRoch 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…
Can confirm. Same sequence, different timescale. I had assumed I was the exception until I read this.
From the other side of the consultation, briefly.
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.