This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Taking post #89 at face value and following it one step further.
Steady state is approached in roughly four to five half-lives. For a compound with a week-long half-life that is four to five weeks, which is where the escalation interval in the trials comes from.
This is the sort of thing the wiki should carry and currently does not.
Loading doses are not used in this class and the pharmacokinetic reason is tolerability rather than efficacy. A loading dose would reach steady state faster and would be intolerable.
That matches what I have seen, for whatever a single anecdote is worth.
I read post #92 twice before replying, because I had assumed the opposite.
Practical note on half-life: write down what you expect before you look. The number of times I have found what I went looking for is higher than chance would allow.
Half-life: semaglutide ≈ 165–184 hours (about a week). Tirzepatide ≈ 5 days. Liraglutide ≈ 13 hours. The half-life determines how much accumulation happens at steady state and how long it takes to clear after stopping.
Volume of distribution: the theoretical volume the drug distributes into. For albumin-binding compounds, volume is reduced compared to drugs that do not bind protein. That is relevant to understanding how much free drug is available.
Narrowing post #94, because the general version has more than one answer.
For anyone finding this later: the short answer on half-life is that it depends on one thing, and the rest of the thread is people identifying which thing.
Everything in post #96 holds. The case it does not cover is the one I have.
Two things can be true about half-life at once: the mechanism is plausible and the evidence for the size of the effect is thin. Most of the argument here is people defending the first against attacks on the second.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
Where I part company with post #96, and it is a narrow parting.
Before the thread moves on from half-life — what is the sample size behind the claim? I am not being difficult; I have seen the same figure quoted from an n of four and from an n of four hundred.
Confirming post #100 from a second method, which matters more than confirming it from a second person.
Half-life determines how quickly concentration approaches steady state and does not determine what the steady-state concentration is. Dose and clearance determine that.
One more thing on half-life that took me far too long to see: the two figures people quote are not measuring the same quantity. Once you notice that, the apparent contradiction disappears.
Noted, and thank you for writing it out rather than summarising it.
Confirming post #103 from a second method, which matters more than confirming it from a second person.
Terminal half-life estimated from a short sampling window underestimates the true value. That is a common source of discrepant figures between sources.
This is the version I would want a new member to read first.
The accumulation ratio for weekly dosing with a week-long half-life is around two, which is why the concentration after several doses is roughly double the concentration after the first.
Happy to be the one who is wrong here if it settles the question.
Washout after stopping takes roughly the same four to five half-lives as reaching steady state. A month after the last dose is not the same as none.
Adding the caveat now so it does not have to be extracted later.
Two questions I would want answered before drawing anything from the half-life data above: how were the cases selected, and what happened to the ones that dropped out.
On post #109 — agreed on the reasoning, with one qualification.
Albumin binding: semaglutide binds albumin through a fatty side chain, which sequesters the free form and extends the half-life. Tirzepatide also has albumin binding (different mechanism) which extends its half-life compared to an unmodified peptide.
Picking up post #109: that is the part I would want checked first.
Accumulation at steady state: with a week-long half-life, steady-state concentration is reached around 4 to 5 half-lives (about 4 to 5 weeks). Before that, concentration is rising with each dose. The clinical implication: escalating before 4 weeks means escalating before steady state.
The confident answers on half-life and the well-sourced answers are not the same answers, which is the most useful thing I have learned reading this category.
Where I have landed on half-life, having got it wrong once in public: the direction is clear, the magnitude is not, and anyone quoting a precise magnitude has borrowed it from somewhere that did not measure it.
A pharmacokinetic model fitted to trial data describes the population studied. Applying it to somebody outside the enrolled range is an extrapolation, and the model will not tell you it is.
I checked the source rather than the summary, and they differ.
This follows post #113 rather than contradicting it.
Metabolism for peptide drugs is proteolytic rather than hepatic in the usual sense, which is why the cytochrome interaction questions that dominate small-molecule pharmacology mostly do not apply.
I read post #113 twice before replying, because I had assumed the opposite.
Half-life: semaglutide ≈ 165–184 hours (about a week). Tirzepatide ≈ 5 days. Liraglutide ≈ 13 hours. The half-life determines how much accumulation happens at steady state and how long it takes to clear after stopping.
Loading doses are not used in this class and the pharmacokinetic reason is tolerability rather than efficacy. A loading dose would reach steady state faster and would be intolerable.
That is what the documentation says. What happens in practice is usually close.
A request rather than an answer: could whoever has the primary source for half-life post it? I have seen the claim three times this month and each version had lost a qualifier.
The useful distinction on half-life is between what was measured and what was inferred from it. Both end up in the same sentence and only one of them has error bars.