Peak-to-trough ratio at steady state for a weekly agent

On the subject in the title: Peak-to-trough ratio at steady state for a weekly agent Working notes rather than a conclusion.

Working through the kinetics rather than the pharmacology, because I think the confusion here is arithmetic.

With a half-life of roughly a week, steady state is approached over four to five half-lives, so anything measured before about a month is measuring a rising concentration. Accumulation at weekly dosing lands the steady-state level near double the first-dose level.

Have I got that right, and does it change what people are actually asking?

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.

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.

Written from notes rather than memory, which is why the numbers are specific.

Narrowing post #2, because the general version has more than one answer.

Small methodological point on peak-to-trough ratio: repeating a measurement is cheap and resolves most of what is being argued about here at no cost to anyone.

No notes. Posting so the count is not one.

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.

On reflection I would soften that slightly.

Post #4 put the caveat in the right place and I want to underline 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.

The evidence for this is thinner than the way I have phrased it suggests.

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 #7 and I disagree about the size of the effect, not about the direction.

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

It is the sort of thing that seems obvious in retrospect and was not at the time.

On peak-to-trough ratio I would separate what is worth knowing from what is worth acting on. The first list is long and the second is short, and conflating them is how threads get heated.

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.

I have changed my mind on this once already, so take it as current rather than settled.

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.