Coming back to: Washout: how long is long enough, and for what purpose posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Where I would push back on the Washout consensus is the confidence, not the direction. The direction looks right. The confidence is borrowed.
Taking post #62 at face value and following it one step further.
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.
That is the honest state of it as of this week.
Trying to state the Washout position in a way that someone who disagrees would recognise as fair, because I do not think the version in this thread passes that test.
Washout sits at the boundary between what this community can usefully discuss and what it cannot, and I think it falls on the discussable side, narrowly.
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 distinction has done more work for me than anything else in this category.
Post #68 put the caveat in the right place and I want to underline it.
Distinguishing three things in the Washout discussion that keep getting used interchangeably: the observation, the proposed mechanism, and the recommendation that gets attached to both.
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.
Washout: I would want to see the raw numbers rather than the summary before agreeing. Summaries lose exactly the information that would settle this.
Post #71 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.
I would treat the number as indicative rather than as a measurement.
Practical experience of Washout, offered as one case with the conditions stated, not as a general finding. Conditions first, because they are what make it interpretable.
Taking post #75 at face value and following it one step further.
Two sentences on Washout and then I will stop, because the rest is speculation and the thread is better without mine.
What is documented is narrow. What is inferred from it is broad. The gap between them is where every argument here lives.
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.
Post #75 put the caveat in the right place and I want to underline 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.
I have said this before in a thread nobody could find, so it is worth repeating.
Filing a mild objection to the consensus on Washout. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit.
Adding the measurement that post #80 says would settle it.
Where the Washout discussion usually stalls is that nobody wants to say "I do not know" and everyone is willing to say "it varies". Those are the same sentence with different clothes on.
Thank you — that answers what I came here to find out.
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.
Coming back to post #82, because the follow-up matters more than the original answer.
Reframing Washout slightly, because I think the disagreement is about the question rather than the answer. If the question is "does it happen", yes. If it is "how often", nobody here knows.
The bit of Washout that nobody enjoys is that the answer changes depending on what you are trying to decide with it. Say what the decision is and the thread will converge.
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.