This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
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.
I would hold that lightly until someone with a larger sample weighs in.
Taking post #59 at face value and following it one step further.
Posting my Half-life numbers with the method attached so they can be discounted properly. Uncontrolled, unblinded, and collected by someone who wanted a particular answer.
The thing about Half-life that took me longest to accept is that a plausible mechanism is not evidence of an effect. It is a reason to look, not a result.
Where two sources give different half-lives, check the study design before deciding either is wrong. Sampling duration, assay sensitivity and population all move the number.
Post #63 put the caveat in the right place and I want to underline it.
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.
I would not lead a decision with this, but I would not ignore it either.
Building on post #63 rather than restating it.
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.
Adding it in case it saves somebody the afternoon it cost me.
Careful with the language on Half-life. "Not detected" and "not present" are different findings and the first is a statement about the method.
Where I part company with post #68, and it is a narrow parting.
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.
Whatever the answer on Half-life turns out to be, the method for getting there is the same: state the assumption, do the arithmetic in public, invite the correction.
Narrowing post #70, because the general version has more than one answer.
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.
One of those cases where knowing the mechanism does not help the decision.
Everything in post #68 holds. The case it does not cover is the one I have.
Subcutaneous absorption is the rate-limiting step for most of these compounds, which is why the apparent half-life is absorption-limited rather than elimination-limited.
I am reporting what happened, not recommending it.
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.
That has held every time I have looked, which is not the same as always.
I keep a log for Half-life specifically because my memory of it turned out to be systematically wrong in one direction. Six weeks of notes cost nothing and settled it.
Post #74 answers the question as asked. The question underneath it is different.
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.
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.
Following this. I have the same question and no better information than the first post.
Worth separating two things that post #76 runs together.
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.
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.
Noted, and thank you for writing it out rather than summarising it.
Thank you — that answers what I came here to find out.
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.
Half-life determines how quickly concentration approaches steady state and does not determine what the steady-state concentration is. Dose and clearance determine that.
This is the version I would want a new member to read first.
The failure mode on Half-life is boring rather than dramatic. It is almost always the step everyone assumes was done correctly because it is too simple to get wrong.
Summarising the Half-life thread so far, since it is long and the answer is buried: the first reply has the method, the fourth has the correction to it, and the rest is people agreeing at length.
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 rule of thumb is fine; the edge cases are where it earns its keep.
Post #85 is right about the mechanism and I think understates the practical bit.
Renal clearance: these compounds are cleared partly via the kidney. In severe renal impairment, clearance is slowed and accumulation risk is higher. Dose adjustments might be needed.
Terminal half-life estimated from a short sampling window underestimates the true value. That is a common source of discrepant figures between sources.
A modest claim, modestly supported.
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 would treat that as a working assumption and revisit it.