Putting this up for argument rather than for agreement. I have read it twice and I am still not certain what it supports.
Splitting does smooth the curve, and that is the problem. With a one-week half-life the weekly curve is already fairly flat — peak-to-trough is modest — so splitting buys very little smoothing while doubling the number of punctures, the number of arithmetic opportunities and the number of chances to lose material to dead space. The people who report a real benefit are usually those whose difficulty is a day-one side effect, which is a peak problem and is the one case where splitting genuinely helps.
Where I think it is weakest: the subgroup findings are the part I trust least — with enough subgroups something is always significant, and these were not all pre-registered.
What I actually want to know is what the pharmacokinetic argument against splitting a weekly dose actually is, since intuitively it should smooth the curve. If the honest answer is that nobody knows, that is a useful answer and I would rather have it.
KarenAZ_mom said:Splitting does smooth the curve, and that is the problem.
Agreed, though "tolerable" needs defining. A dose you tolerate by eating almost nothing is not tolerated, it is being paid for somewhere else — usually in lean mass, sometimes in adherence three months later.
Happy to go further on any of that.
KarenAZ_mom said:Splitting does smooth the curve, and that is the problem.
Filing a mild objection. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit. Halving the dose and calling it splitting is not the same intervention, and this thread keeps mixing them. One changes the schedule; the other changes the exposure.
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Shop Reference StandardsTaking the question as asked, rather than the general version of it. Albumin binding above 99% is the whole reason weekly dosing works, and it is also why the trough matters more than the peak. People who dose late are not losing a peak, they are letting the trough fall, and the appetite effect tracks the trough.
HPLC_Greg said:Agreed, though "tolerable" needs defining.
All true, with one condition: that curve is for people who reached the dose on schedule. Anyone who slowed the ladder for tolerability is on a different, flatter curve, and comparing yourself with the published mean will make you feel like a non-responder when you are not.