PK/PD modeling for tirzepatide — receptor occupancy calculations

Adding the numbers, since they settle part of this. 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.

Worth separating that from the pharmacology, which this thread keeps folding into the same question. They behave differently and the advice does not transfer.

A narrower follow-up, since the general answer is now clear:

Whether anyone has held 10mg long term rather than climbing, and what happened over the following year?

labquiet_amy said:

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…

Coming at labquiet_amy’s question from a different direction. 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.

Closing the loop on my own question.

Update: the eight-week restart pattern people described is exactly what happened. I nearly abandoned it at week five.

julia.endo said:

The mechanism is more central than most summaries suggest.

Agreed on the mechanism, with the caveat that the head-to-head used semaglutide 1mg, not 2.4mg. It is still the best direct evidence available, but it is not the comparison most people think they are citing.