Peak-to-trough ratio at steady state for a weekly agent — the long version posts 31–60
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
I think the Peak-to-trough ratio question is answerable and has not been answered, which is a more optimistic position than most of this thread.
On post #30 — agreed on the reasoning, with one qualification.
Where the Peak-to-trough ratio reasoning breaks down for me is the step from the group result to the individual case. That step is almost never argued for.
Post #33 is right about the mechanism and I think understates the practical bit.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
The most useful thing anyone has posted about Peak-to-trough ratio in this category was a table of what had been measured and by whom. That is what I would want again.
I would rather this thread reach "we do not know" about Peak-to-trough ratio than reach a confident answer that nobody can support when asked.
Marking my place. If it changes for me I will come back and say so.
Post #38 put the caveat in the right place and I want to underline it.
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.
A request rather than an answer: could whoever has the primary source for Peak-to-trough ratio post it? I have seen the claim three times this month and each version had lost a qualifier.
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 have kept the units in throughout, for the obvious reason.
Post #40 describes the usual case. This is about the unusual one.
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.
Small point, but it is the one that usually catches people.
Adding the measurement that post #43 says would settle it.
What would change my mind on Peak-to-trough ratio is a second dataset collected by someone with no stake in the first. Until then I hold it loosely and I would rather say so than pretend to more.
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.
Worth one more sentence than it usually gets.
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.
Post #47 and I disagree about the size of the effect, not about the direction.
On Peak-to-trough ratio, the part that usually goes wrong is that the question is asked as though it has one answer. It has a range, and the width of the range is the interesting bit.
If you can post the two or three numbers you are working from, several people here will check the arithmetic rather than argue about the conclusion.
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.
If this contradicts something upthread, the upthread version may well be the better 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.
Noted, and thank you for writing it out rather than summarising it.
I would call the community position on Peak-to-trough ratio likely rather than established, and I would be comfortable defending that hedge.
Building on post #54 rather than restating it.
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 #53 put the caveat in the right place and I want to underline it.
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.
If it helps: the failure mode here is usually boring rather than dramatic.
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.
Agreed on all of that, and I have nothing to add to it.