Pharmacology · Pharmacokinetics · continued

Coming back to: Time to steady state after a dose increase posts 91–111

Pharmacology › Pharmacokinetics semaglutide missed dose liraglutide worked example

This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.

d.ndiayeTL22 Jul 2026#91

e.ferreira, post #70: 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. Posted with less confidence than the sentence structure implies. Go to post

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.

I have deliberately not rounded that, because the rounding is where the argument starts.

30 likes in reply to #70 26d

WickramasingheTL2Member4 Jul 2026 · edited#92

d.ndiaye, post #91: 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. I have deliberately not rounded that, because the rounding is where the argument starts. Go to post

The time to maximum concentration after a subcutaneous dose in this class is measured in days rather than hours, which surprises people expecting an injection to act quickly.

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

0 likes in reply to #91 24d

m.dumitruTL25 Jul 2026#93

Post #90 answers the question as asked. The question underneath it is different.

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.

6 likes 23d

ZieglerTL3Regular6 Jul 2026#94

I read post #92 twice before replying, because I had assumed the opposite.

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.

15 likes 22d

b.jansenTL27 Jul 2026#95

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

That is a description of practice, not a recommendation of it.

22 likes 21d

baseline_peakTL2Member8 Jul 2026#96

r.venkatesan, post #10: 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. Go to post

This settles it for me, at least until somebody posts a reason it should not.

0 likes in reply to #10 19d

b.nwosuTL210 Jul 2026#97

Narrowing post #94, because the general version has more than one answer.

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.

Not the answer, but possibly the question that gets there.

3 likes 18d

m.stephanopoulosTL3Regular11 Jul 2026#98

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.

I have kept the units in throughout, for the obvious reason.

10 likes 17d

s.demirTL212 Jul 2026#99

Collapsed as off-topic by two members at trust level 3 or above

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.

RidgewayTL3Regular13 Jul 2026#100

s.dziedzic, post #78: 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. Go to post

On post #97 — agreed on the reasoning, with one qualification.

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.

31 likes in reply to #78 15d

e.adeyemiTL214 Jul 2026#101

j.baptista, post #28: 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. I would be glad to be shown a cleaner way of putting this. Go to post

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

It is the kind of thing that is obvious once and never again.

23 likes in reply to #28 13d

g.tanakaTL3Regular16 Jul 2026#102

Between-person variability in exposure is substantial and is the reason two people on the same dose can have quite different plasma concentrations. That is inherent rather than a formulation defect.

0 likes 12d

e.mbekiTL217 Jul 2026#103

Thank you for taking the time. That was more work than a reply usually is.

1 like 11d

revision_historyTL3Wiki editor18 Jul 2026#104

Worth separating two things that post #102 runs together.

Happy to expand any of that if it is the useful part.

6 likes 10d

m.ilungaTL219 Jul 2026#105

r.novak, post #40: Post #39 put the caveat in the right place and I want to underline it. 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. Someone will know this better than I do and I hope they say so. Go to post

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.

16 likes in reply to #40 9d

m.ferrandTL1Member20 Jul 2026 · edited#106

Coming back to post #102, because the follow-up matters more than the original answer.

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.

32 likes 7d

s.teixeiraTL222 Jul 2026#107

Picking up post #104: 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.

That is all the detail I have. Someone else will have more.

0 likes 6d

desiccant_notesTL2Member23 Jul 2026#108

Loading doses are not used in this class and the pharmacokinetic reason is tolerability rather than efficacy. A loading dose would reach steady state faster and would be intolerable.

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

3 likes 5d

s.roosTL224 Jul 2026#109

The arithmetic in post #108 is right; the assumption feeding it is the part to check.

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.

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

11 likes 4d

g.valckenaereTL3Regular25 Jul 2026#110

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.

I would put the burden of proof on the interesting explanation, not the dull one.

24 likes 3d

i.beaulieuTL226 Jul 2026#111

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.

15 likes 2d

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Coming back to: Time to steady state after a dose increase posts 91–111

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