This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Worth separating two things that post #57 runs together.
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.
The honest answer on half-life is that it depends, and the useful part is the list of what it depends on. Four items, in rough order of how much they matter.
Most people get the first two right and then argue about the fourth.
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.
Not the answer, but possibly the question that gets there.
I read the earlier replies on half-life twice before writing this, because I had assumed the opposite and wanted to be sure I was disagreeing with what was said rather than what I expected.
Counterpoint on half-life, offered without confidence: the same observation is consistent with a much duller explanation, and nobody has ruled the dull one out.
Post #66 answers the question as asked. The question underneath it is different.
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.
Adding the measurement that post #69 says would settle it.
I would call the community position on half-life likely rather than established, and I would be comfortable defending that hedge.
Post #70 describes the usual case. This is about the unusual one.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
Confirming post #72 from a second method, which matters more than confirming it from a second person.
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.
No disagreement from me. Posting only so the question does not look ignored.
Half-life determines how quickly concentration approaches steady state and does not determine what the steady-state concentration is. Dose and clearance determine that.
The short version is the first sentence; the rest is why.
What I want from this half-life thread is the list of things that would need to be true for the claim to hold. If we can write that list, we can check it.
Post #76 is right about the mechanism and I think understates the practical bit.
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.
Coming back to post #75, because the follow-up matters more than the original answer.
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.
Narrowing post #76, 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.
I would put this at better than even and not much better.
Terminal half-life estimated from a short sampling window underestimates the true value. That is a common source of discrepant figures between sources.
Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki.
Taking post #79 at face value and following it one step further.
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.
Take it as a starting point and not as a specification.
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.
Worth separating two things that post #83 runs together.
Half-life: I have looked for the primary source twice and failed twice. Either it does not exist or it is somewhere I do not know to look, and I would like to know which.
This follows post #83 rather than contradicting it.
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.
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.
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.
Stating my assumptions rather than smuggling them in.
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.