d.petrescu, post #6: No notes. Posting so the count is not one. Go to post
Right — I had this wrong and I am glad to have read it before it mattered.
Pharmacology · Pharmacokinetics · continued
Peak-to-trough ratio at steady state for a weekly agent posts 31–60
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
Everything in post #29 holds. The case it does not cover is the one I have.
The strongest argument against my own position on peak-to-trough ratio, stated as well as I can state it, since nobody else has yet.
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Distinguishing three things in the peak-to-trough ratio discussion that keep getting used interchangeably: the observation, the proposed mechanism, and the recommendation that gets attached to both.
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m.ramos, post #22: Half-life determines how quickly concentration approaches steady state and does not determine what the steady-state concentration is. Dose and clearance determine that. I would call that likely rather than established. Go to post
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.
Building on post #33 rather than restating it.
What I would tell a new member reading about peak-to-trough ratio for the first time: the confident posts are not the reliable ones, and the reliable ones are longer.
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l.vermeulen, post #36: Building on post #33 rather than restating it. What I would tell a new member reading about peak-to-trough ratio for the first time: the confident posts are not the reliable ones, and the reliable ones are longer. Go to post
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
Where I part company with post #37, and it is a narrow parting.
Peak-to-trough ratio looks different depending on whether you are reading the primary literature or the summaries of it, and the difference is not in our favour.
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Fair, and the limits you put on it are the part I will remember.
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The confident answers on peak-to-trough ratio and the well-sourced answers are not the same answers, which is the most useful thing I have learned reading this category.
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IMainwaring, post #35: 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. Go to post
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.
Confirming post #42 from a second method, which matters more than confirming it from a second person.
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.
The disagreement above is smaller than it looks once the terms are fixed.
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I had written a reply contradicting post #41 and deleted it. Here is what survived.
Worth separating peak-to-trough ratio as a question about the compound from peak-to-trough ratio as a question about the documentation. They get answered by different people and only one of them is answerable here.
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l.lundgren, post #34: Distinguishing three things in the peak-to-trough ratio discussion that keep getting used interchangeably: the observation, the proposed mechanism, and the recommendation that gets attached to both. Go to post
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.
That matches what I have seen, for whatever a single anecdote is worth.
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This follows post #46 rather than contradicting 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.
That much is documented. The rest is how I have interpreted it.
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i.coelho, post #3: 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. Go to post
Worth separating two things that post #48 runs together.
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.
The step people skip is the one I have spelled out.
Same experience here, different supplier, so it is at least not unique to one of them.
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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 number is defensible. The precision I gave it is not.
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curious_reader, post #21: Narrowing post #20, because the general version has more than one answer. 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. Go to post
Confirming post #52 from a second method, which matters more than confirming it from a second person.
The practical version of peak-to-trough ratio is three sentences long. The rigorous version is three pages and reaches the same conclusion with the conditions attached.
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.
Flagging that the sources on this are thinner than the confidence in the thread suggests.
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t.kulkarni, post #47: That matches what I have seen, for whatever a single anecdote is worth. Go to post
Post #55 is the version of this I will quote in future. One addition.
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 #55 and I disagree about the size of the effect, not about the direction.
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 be precise about what I do not know than vague about what I do.
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