Time to steady state after a dose increase posts 151–164

The arithmetic in post #150 is right; the assumption feeding it is the part to check.

The accumulation ratio for weekly dosing with a week-long half-life is around two, which is why the concentration after several doses is roughly double the concentration after the first.

This is the sort of thing that ought to be settled and apparently is not.

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.

Two sources, same conclusion, and I could not rule out that one copied the other.

Useful. I have added it to my own notes with the date on it.

Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.

Worth reading the earlier posts in this thread before acting on mine.

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.

Dose proportionality across the studied range means dose arithmetic behaves the way you would naively expect. It is worth checking whether it holds for a given compound rather than assuming.

Post #156 and I disagree about the size of the effect, not about the direction.

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.

Half-life: semaglutide ≈ 165–184 hours (about a week). Tirzepatide ≈ 5 days. Liraglutide ≈ 13 hours. The half-life determines how much accumulation happens at steady state and how long it takes to clear after stopping.

Fasting requirement for oral semaglutide: food and large fluid volumes reduce absorption. The fasting window (30 minutes before and 30 minutes after) is designed to maximise absorption. Violating it measurably reduces exposure.

Worth separating two things that post #157 runs together.

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.

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.

For what it is worth, the same held on the two occasions I checked.

That reframing is the whole thing. The facts I already had.

Post #161 is right about the mechanism and I think understates the practical bit.

Steady state is approached in roughly four to five half-lives. For a compound with a week-long half-life that is four to five weeks, which is where the escalation interval in the trials comes from.