This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Post #88 answers the question as asked. The question underneath it is different.
Escalating before steady state means you are judging a dose you have not yet fully experienced. That is the whole argument against compressing the schedule and it is a good one.
I would be interested in a counterexample if anyone has one.
I read post #90 twice before replying, because I had assumed the opposite.
Offering a way to settle steady state rather than another opinion about it. Two measurements, taken the same way, a fortnight apart. If the difference is within the noise, the question was not answerable at this precision.
On steady state I would separate what is worth knowing from what is worth acting on. The first list is long and the second is short, and conflating them is how threads get heated.
Concentration and dose get conflated constantly in this subcategory. Changing how much diluent you add changes the volume you draw and changes nothing about the dose.
Counterpoint on steady state, offered without confidence: the same observation is consistent with a much duller explanation, and nobody has ruled the dull one out.
Steady state means the plasma concentration is stable from dose to dose. That happens around 4 to 5 half-lives. Before that, the concentration is rising with each dose. Escalating before steady state means escalating on incomplete information about the dose you are on.
Building on post #102 rather than restating it.
Steady state is a question about a distribution, not about a value, and treating it as a value is what produces the confident wrong answers.
Post #100 put the caveat in the right place and I want to underline it.
I would call the community position on steady state likely rather than established, and I would be comfortable defending that hedge.
Half steps are arithmetically simple and pharmacologically unstudied. They are not dangerous in any obvious way and they are also not what the evidence describes, and both halves of that should be said.
That is the shape of it. The detail is where I would expect to be corrected.
Concentration and dose get conflated constantly in this subcategory. Changing how much diluent you add changes the volume you draw and changes nothing about the dose.
The general case is well covered; this is the awkward specific one.
Post #106 is the version of this I will quote in future. One addition.
There is no published evidence about slower escalation because nobody studied it. That means the trials support not going faster and are silent on going slower, which is a different claim from "slower is fine".
Reporting rather than recommending, on steady state. What happened is above. Whether it should have is a different question and not one I am qualified to answer.
Concentration and dose get conflated constantly in this subcategory. Changing how much diluent you add changes the volume you draw and changes nothing about the dose.
Filing this under things that are true until someone shows me otherwise.
This is the first time the answer has come with its own limits attached. Appreciated.
I disagree with the framing of steady state above, and I think it is a substantive disagreement rather than a terminological one. Setting out why, so it can be checked.
The reasoning depends on an assumption that is doing a lot of work and is never stated. If the assumption holds, the conclusion follows. I do not think it holds generally.
Source for the steady state figure, since it was asked for. It is in the discussion rather than the abstract, which is why the version circulating is stronger than the paper is.
Reading the surrounding paragraph is worth the two minutes. The authors are more careful than their summarisers.
Where I part company with post #111, and it is a narrow parting.
Split dosing within a week is sometimes proposed to smooth tolerability. With a week-long half-life the concentration is already smooth, so what it would change is the timing of the peak rather than its existence.
Same experience here, different supplier, so it is at least not unique to one of them.
The useful distinction on steady state is between what was measured and what was inferred from it. Both end up in the same sentence and only one of them has error bars.
I had written a reply contradicting post #116 and deleted it. Here is what survived.
Concentration and dose get conflated constantly in this subcategory. Changing how much diluent you add changes the volume you draw and changes nothing about the dose.
The right answer here may simply be that it has not been measured.
Narrowing post #119, because the general version has more than one answer.
Holding at a dose that is working is a legitimate position and it is not what the trial protocols did. The protocols escalated to a target because they were measuring the target dose, not finding each person's minimum.
Take it as a starting point and not as a specification.