Splitting a weekly dose in two: the pharmacokinetic argument against — the long version

I had read the opposite somewhere and cannot now find where, which tells me something.

Holding a dose indefinitely: the trials did not study indefinite holding at a non-maximum dose. The trials escalated to a target and then held that. What happens if you stay at an intermediate dose for years is not formally studied and extrapolation is the best available reasoning.

Adding a null result on Splitting a weekly dose. I looked, carefully, and found nothing, and null results deserve posting precisely because they never are.

Confirming post #17 from a second method, which matters more than confirming it from a second person.

The strongest argument against my own position on Splitting a weekly dose, stated as well as I can state it, since nobody else has yet.

I read post #17 twice before replying, because I had assumed the opposite.

If you are stepping up mainly because the schedule says so rather than because the current dose has stopped doing what you wanted, that is worth noticing before rather than afterwards.

I would hold that lightly until someone with a larger sample weighs in.

Post #17 answers the question as asked. The question underneath it is different.

The four-week escalation interval is a convention from the pivotal trials, not a pharmacological constant. The pharmacological argument is that with a week-long half-life, four weeks approaches steady state and you can assess the dose fairly. That is an argument for not going faster. It is not an argument against going slower.

Fair, and the limits you put on it are the part I will remember.

I read the earlier replies on Splitting a weekly dose 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.

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.

That is the practical version. The rigorous version is longer and says the same thing.

Where I part company with post #20, and it is a narrow parting.

Reaching a dose and staying there for a year: the question of whether a stable dose remains effective over years is mostly answered by the withdrawal trials and by real-world reports. The dose does not seem to stop working, but the longest trials are not indefinitely long.

The confident version of this sentence would be wrong, so here is the hedged one.

Adding the measurement that post #22 says would settle it.

Worth stating the null on Splitting a weekly dose before we explain it: the observation may be nothing. That possibility deserves a sentence and usually does not get one.

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.

Dose and effect are not linear across the studied range for every compound in this class. Assuming a doubled dose gives a doubled effect is the reasoning error behind most disappointment.

Adding it in case it saves somebody the afternoon it cost me.

Going back down a step is not a failure and the trials allowed it. Several protocols permitted a return to the previous dose for tolerability and then a second attempt at the step.

I would not lead a decision with this, but I would not ignore it either.

Picking up post #26: that is the part I would want checked first.

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.

The short version is the first sentence; the rest is why.

Agreed, and I will stop repeating the version of this I had been repeating.