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Evidence-based GLP-1 & peptide discussion since 2023
ForumsPharmacology & MechanismsMolecular dynamics simulations of GLP-1R binding — anyone have experience?

Molecular dynamics simulations of GLP-1R binding — anyone have experience?

SkepticalSean Mon, Jul 22, 2024 at 8:00 AM 47 replies 3,019 viewsPage 1 of 10
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SkepticalSean
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Jul 22, 2024 at 8:00 AM#1

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.

What I am after 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.

2 22DerekSJ_a1c, paige_pharma
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TrialTracker_MD
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Jul 22, 2024 at 8:05 AM#2
SkepticalSean 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.

Last edited: Jul 22, 2024 at 1:05 PM
1 21stefan_berlin
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traveltech_sara
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Jul 22, 2024 at 8:10 AM#3
TrialTracker_MD said:
PK/PD modeling for the pharmacology: understanding the pharmacokinetics helps optimize dosing.

Agreeing with TrialTracker_MD, 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.

50 20wanda_boise, NurseAsh_DET, BenResearch_OR and 47 others
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patPC_UT
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Jul 22, 2024 at 8:15 AM#4
SkepticalSean 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.

49 19JessicaM_2024, TomFromTexas, mike.trainer_LA and 46 others
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Dr.Martinez
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Jul 22, 2024 at 8:42 AM#5

Clinical perspective, offered as context rather than as advice.

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.

References:
[1] Novo Nordisk investor presentation, September 2023.
Last edited: Jul 22, 2024 at 1:42 PM
48 18adam_van, Dr.SurgeonPGH, rachel_ABQ and 45 others
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