This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
The version of Washout that circulates here is a simplification of a simplification. It is not wrong, but it has lost the conditions under which it holds, and those conditions are where the interesting cases live.
Acknowledging rather than arguing. The reasoning holds as far as I can follow it.
On post #90 — agreed on the reasoning, with one qualification.
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.
Taking Washout seriously for a moment rather than deflecting: the honest position is that the community has observations and no controlled comparison, and those two things support very different sentences.
The reason Washout keeps being re-asked is that the answer is conditional and people quote it without the condition. It is not that the answer is unknown.
Marking my uncertainty on Washout explicitly. I am confident about the direction, much less confident about the size, and not confident at all that it generalises past the case in the first post.
That is consistent with mine, for whatever one more account is worth.
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.
Reading rather than contributing, but this is the most useful thread I have found on it.
My position on Washout is current rather than settled. I have revised it once already and I expect to again, so treat it accordingly.
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.
Not a conclusion. A place to stand while looking for one.
A note on how Washout gets discussed rather than on Washout itself: the confident posts get the replies and the careful ones get ignored, and the careful ones have been right more often.
On post #105 — agreed on the reasoning, with one qualification.
I read the earlier replies on Washout twice before writing this, because I had assumed the opposite and wanted to be sure I was disagreeing with what was said rather than what I expected.
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
Noting that the question and the thing people usually mean by it are different.
I had written a reply contradicting post #105 and deleted it. Here is what survived.
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.
If that reads as pedantic, it is, and it has saved me twice.
Reporting rather than recommending, on Washout. What happened is above. Whether it should have is a different question and not one I am qualified to answer.
Confirming post #108 from a second method, which matters more than confirming it from a second person.
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 kept the units in throughout, for the obvious reason.
Careful with the language on Washout. "Not detected" and "not present" are different findings and the first is a statement about the method.
Two questions I would want answered before drawing anything from the Washout data above: how were the cases selected, and what happened to the ones that dropped out.
On post #110 — agreed on the reasoning, with one qualification.
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.
Small point, but it is the one that usually catches people.
Post #112 is the version of this I will quote in future. One addition.
Adding a small correction to the Washout summary above rather than a disagreement with it. The substance holds; one of the figures is out by a factor that matters.
The thing about Washout that took me longest to accept is that a plausible mechanism is not evidence of an effect. It is a reason to look, not a result.
Post #118 put the caveat in the right place and I want to underline it.
Washout is a good example of a question where the honest answer is boring and the interesting answers are unsupported. I would go with boring.