Peak-to-trough ratio at steady state for a weekly agent — the long version Writing it up because I had to work it out twice and would rather nobody else did.
A narrow question about Peak-to-trough ratio, deliberately narrow, because the broad version has been asked here four times and produced four long threads and no answer.
One question, stated units, stated method, and what I have already ruled out.
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 holds under the stated conditions and I have stated them.
I came in to disagree and I am leaving without a disagreement.
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 read post #5 twice before replying, because I had assumed the opposite.
I would put moderate confidence on the mainstream reading of Peak-to-trough ratio and no more. That is not scepticism for its own sake; it is where the sourcing actually stops.
Post #5 answers the question as asked. The question underneath it is different.
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.
That has held every time I have looked, which is not the same as always.
Useful. I have added it to my own notes with the date on it.
Adding the measurement that post #7 says would settle it.
Before the thread moves on from Peak-to-trough ratio — 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.
The arithmetic on Peak-to-trough ratio is the easy part and it is where the errors are, which is an uncomfortable combination. Show your working and someone will catch it.
Where I part company with post #10, and it is a narrow parting.
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.
The strength of my opinion here exceeds the strength of my evidence.
If you are new and reading this thread for the answer to Peak-to-trough ratio: the answer is conditional, the conditions are in the third reply, and the rest of the thread is worth skipping.
A note on how Peak-to-trough ratio gets discussed rather than on Peak-to-trough ratio itself: the confident posts get the replies and the careful ones get ignored, and the careful ones have been right more often.
That is the distinction I keep failing to hold on to. Written down now.
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.
Taking post #18 at face value and following it one step further.
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.
I would rather be precise about what I do not know than vague about what I do.
A missed weekly dose perturbs a slowly moving average rather than creating a trough. That is the pharmacokinetic reason the labelling does not recommend doubling.
The rule of thumb is fine; the edge cases are where it earns its keep.
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 treat the number as indicative rather than as a measurement.
This follows post #21 rather than contradicting it.
The number people quote for Peak-to-trough ratio is a central estimate presented without its interval, and the interval is wide enough that the estimate is nearly uninformative on its own.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
This is the version I would want a new member to read first.
Quietly grateful for the plain phrasing. Not every thread gets that.
A definition problem is doing most of the work in this Peak-to-trough ratio discussion. Once the term is pinned down I suspect the disagreement mostly goes away and what is left is small.
I had written a reply contradicting post #25 and deleted it. Here is what survived.
Peak-to-trough ratio: I would want to see the raw numbers rather than the summary before agreeing. Summaries lose exactly the information that would settle this.
Confirming post #29 from a second method, which matters more than confirming it from a second person.
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.