Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience both.
What I actually want to know is which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.
I would rather have one careful answer than five confident ones.
PharmD_Rodriguez said:Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…
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.
sarah.morrison 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 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.
Happy to go further on any of that.
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Browse GL BiochemPharmD_Rodriguez said:Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…
Can confirm. Same sequence, different timescale.
From the other side of the consultation, briefly.
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.