Half-life, steady state, and accumulation worked through

Narrowing post #14, because the general version has more than one answer.

Adding the boring version of half-life, because the interesting version keeps getting posted and the boring one is usually right.

Check the ordinary explanations, in order, and stop when one of them accounts for what you are seeing. Most of the time the second one does.

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.

I would treat that as a working assumption and revisit it.

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.

Filing this under things that are true until someone shows me otherwise.

No notes. Posting so the count is not one.

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.

I would rather post the uncertainty than round it away.

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.

If anyone can point at the primary source I would be grateful.

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.

The general case is well covered; this is the awkward specific one.

Half-life determines how quickly concentration approaches steady state and does not determine what the steady-state concentration is. Dose and clearance determine that.

That is the shape of it. The detail is where I would expect to be corrected.

Noted, and I have changed what I was going to do on the strength of it.

Post #21 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.

Speaking only to half-life as I have actually seen it, rather than as it is usually described: the effect is real, it is smaller than the thread suggests, and the variance between people is larger than the effect.

I disagree with the framing of half-life above, and I think it is a substantive disagreement rather than a terminological one. Setting out why, so it can be checked.

The reasoning depends on an assumption that is doing a lot of work and is never stated. If the assumption holds, the conclusion follows. I do not think it holds generally.

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.

Half-life is one of those subjects where the general answer and the answer for a specific case diverge, and the thread will go in circles until someone says which one is being asked for.

Building on post #29 rather than restating 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.