Good question, well framed, and I would like to see it answered properly.
2 likes 21mo
Pharmacology · Pharmacokinetics · continued
Time to steady state after a dose increase posts 121–150
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
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.
0 likes 21mo
Post #122 and I disagree about the size of the effect, not about the direction.
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.
Genuinely open to being wrong about this one.
29 likes 21mo
n.rowntree, post #72: 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. Posting it because the silence on this was starting to look like agreement. Go to post
Taking post #122 at face value and following it one step further.
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.
Not disagreeing with anyone above, just adding the bit I keep having to look up.
I read post #122 twice before replying, because I had assumed the opposite.
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.
It took me longer than it should have to see that.
1 like 21mo
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.
Filing this under things that are true until someone shows me otherwise.
0 likes 21mo
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.
21 likes 21mo
system_suitability, post #87: 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 follows post #125 rather than contradicting it.
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.
That is a description of practice, not a recommendation of it.
r.frisk, post #6: 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. That distinction has done more work for me than anything else in this category. Go to post
Coming back to post #125, because the follow-up matters more than the original answer.
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.
Post #128 is right about the mechanism and I think understates the practical bit.
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.
It is worth checking rather than assuming, which costs nothing.
23 likes 21mo
m.adebayo, post #79: Everything in post #78 holds. The case it does not cover is the one I have. 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. Nothing above should be read as advice about what anyone else should do. Go to post
Coming back to post #131, because the follow-up matters more than the original answer.
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.
This has been discussed before and I could not find the thread, so, again.
Thank you for taking the time. That was more work than a reply usually is.
1 like 21mo
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
7 likes 21mo
n.laurent, post #65: Picking up post #63: 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. Go to post
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.
s.oyelaran, post #96: 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. A weak preference rather than a position. Go to post
I had written a reply contradicting post #134 and deleted it. Here is what survived.
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.
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.
Adding a source would improve this post and I do not have one to hand.
0 likes 21mo
glossary_desk, post #24: Coming back to post #22, because the follow-up matters more than the original answer. 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… Go to post
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.
I have kept the units in throughout, for the obvious reason.
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.
24 likes 21mo
weekly_pin, post #30: Post #26 describes the usual case. This is about the unusual one. 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. I would put a moderate confidence on that and no more. Go to post
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.
The arithmetic in post #139 is right; the assumption feeding it is the part to check.
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.
The uncertainty is in the assumption, not in the calculation.
26 likes 21mo
m.steiner, post #63: 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. Adding it in case it saves somebody the afternoon it cost me. Go to post
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
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.
Small point, but it is the one that usually catches people.
0 likes 21mo
Body weight affects volume of distribution and therefore exposure at a fixed dose. Whether that translates into a dosing implication depends on the width of the therapeutic window.
It is one reading of the data and not the only reasonable one.
19 likes 21mo
I had written a reply contradicting post #143 and deleted it. Here is what survived.
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.
The interesting part of this is the exception, and I do not understand the exception.
5 likes 21mo
vial_desk, post #80: Narrowing post #78, because the general version has more than one answer. 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
Confirming post #147 from a second method, which matters more than confirming it from a second person.
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.
l.cabrera, post #1: On the subject in the title: Time to steady state after a dose increase Working notes rather than a conclusion. Working through the kinetics rather than the pharmacology, because I think the confusion here is arithmetic. With a half-life of roughly a week, steady state is approached over four to five half-lives, so anything measured… Go to post
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.
septum_entry, post #117: 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. Marking that as an opinion rather than a finding. Go to post
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.