Time to steady state after a dose increase posts 31–60

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.

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.

Take the reasoning and check the arithmetic; I do not always get it right.

Picking up post #46: that is the part I would want checked first.

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.

That is what I would do. It may not be what is correct.

On post #45 — agreed on the reasoning, with one qualification.

A missed weekly dose perturbs a slowly moving average rather than creating a trough. That is the pharmacokinetic reason the labelling does not recommend doubling.

Same conclusion as the reply above, reached differently, which is mildly reassuring.

Taking post #46 at face value and following it one step further.

Bioavailability: oral semaglutide has low bioavailability (roughly 1%) due to peptide instability. That is why the oral dose (14 mg) is so much larger than the injectable dose. Comparing them by mass is meaningless.

Written from notes rather than memory, which is why the numbers are specific.

Post #48 and I disagree about the size of the effect, not about the direction.

Individual variation: people vary in how quickly they absorb, distribute, metabolise, and excrete these compounds. That variation is partly genetic and partly due to individual biology (gut motility, kidney and liver function). It explains why two people on the same dose have different response magnitudes.

A modest claim, modestly supported.

Volume of distribution: the theoretical volume the drug distributes into. For albumin-binding compounds, volume is reduced compared to drugs that do not bind protein. That is relevant to understanding how much free drug is available.

Where two sources give different half-lives, check the study design before deciding either is wrong. Sampling duration, assay sensitivity and population all move the number.

On post #51 — agreed on the reasoning, with one qualification.

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.

Adding it because I spent an afternoon working it out and nobody should have to twice.

Picking up post #51: that is the part I would want checked first.

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.

The claim is narrower than it sounds, and deliberately so.

Accumulation at steady state: with a week-long half-life, steady-state concentration is reached around 4 to 5 half-lives (about 4 to 5 weeks). Before that, concentration is rising with each dose. The clinical implication: escalating before 4 weeks means escalating before steady state.

If anyone can point at the primary source I would be grateful.

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

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.

This follows post #55 rather than contradicting it.

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.

None of the above is medical advice and I am not qualified to give any.

Where I part company with post #55, and it is a narrow parting.

Half-life determines how quickly concentration approaches steady state and does not determine what the steady-state concentration is. Dose and clearance determine that.

Not a strong opinion, just a consistent one.

Post #59 is the version of this I will quote in future. One addition.

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.

If anyone has run this properly I would rather read that than my own guess.