Titration schedule reference

The label ladders, side by side

The structure is identical across the class and across indications: a sub-therapeutic starting dose that exists purely for tolerability, fixed-interval steps, a maintenance range rather than a single target, and a defined ceiling above which nothing was studied. Read that pattern once and the individual ladders stop needing to be memorised.

Why four weeks

Because four weeks is approximately steady state for a compound with a seven-day elimination half-life, and escalating before steady state means escalating onto a still-rising concentration.

The accumulation ratio for weekly dosing at a seven-day half-life is 1 / (1 − 0.5) = 2: at steady state your trough is about twice what a single dose would produce. Reaching within a few per cent of that takes four to five half-lives, hence four to five weeks. A four-week step interval therefore has you escalating at roughly 94 per cent of the previous dose's steady state — close enough to be sensible, not so close as to be timid.

Compressing the interval to two weeks means each step lands at 75 per cent of the previous plateau, so the concentration rise from the new dose stacks on top of a rise still in progress. The published gastrointestinal adverse-event curves cluster in the one to two weeks after each increase, which is exactly the window a compressed ladder puts under additional load.

Vial-day arithmetic

Converting a schedule into how long a vial lasts, which is the question people actually have. Worked for a 10 mg vial reconstituted to 2 mL, so 5 mg/mL, using a fixed-needle insulin syringe with 4 µL of dead space.

Two things fall out of that table. First, at low doses the dead space is a rounding error and at 0.25 mg it costs you nothing worth measuring; the loss becomes proportionally invisible as the draw gets larger, which is the opposite of what people expect. Second, the annual vial count scales with the dose almost linearly, so the twelve-month cost of a course is dominated by where on the ladder you end up rather than by how you got there.

What the protocols did about intolerance

The trial protocols in this class generally permitted a step to be delayed, and in several cases to be reduced, for intolerance — and a non-trivial minority of participants used that provision. This matters for how the headline results should be read: the reported mean weight change is not the result of everyone reaching the top of the ladder on schedule. It is the result of a population in which some people did and some people did not, analysed under a stated estimand.

It also matters for the common inference that failing to tolerate the top dose means failing to get the benefit. The maintenance ranges in the table above are ranges precisely because more than one dose produced a clinically meaningful result.

Where the arithmetic stops helping

• Inter-individual exposure varies substantially at a fixed dose. The ladder exists partly because a single population dose would over-expose some people and under-expose others.
• Tolerating a dose easily is not evidence that you need a higher one. These are separate questions and they get conflated constantly.
• A plateau is not a titration signal. Weight loss curves flatten in every trial in the class because energy expenditure falls with mass. That is arithmetic, not tachyphylaxis.
• None of this applies to unapproved agents. There is no label ladder for a tri-agonist in Phase 3, and Phase 2 dose-ranging is not a schedule.

Related tags: titration444

titration

Stepwise dose increases over weeks, why the label schedules exist at all, and what tolerability-driven deviation from a schedule looks like in…