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.
31 likes 21mo
Pharmacology · Pharmacokinetics · continued
Time to steady state after a dose increase posts 91–120
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
e.steiner, post #86: 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. Go to post
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.
l.osei, post #57: 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. Go to post
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.
Noting that I have skin in this question and have tried to discount for it.
Picking up post #91: that is the part I would want checked first.
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.
Adding the caveat now so it does not have to be extracted later.
0 likes 21mo
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.
11 likes 21mo
h.frisk, post #69: Adding the measurement that post #68 says would settle it. 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 am reporting what happened, not recommending it. Go to post
Post #95 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 have changed my mind on this once already, so take it as current rather than settled.
Collapsed as off-topic by two members at trust level 3 or above
Adding the measurement that post #95 says would settle it.
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 am aware this is the third time this month I have made this point.
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.
I looked this up rather than remembered it, which is the right order.
17 likes 21mo
Post #99 is the version of this I will quote in future. One addition.
Renal clearance: these compounds are cleared partly via the kidney. In severe renal impairment, clearance is slowed and accumulation risk is higher. Dose adjustments might be needed.
That is where I would start, not where I would stop.
7 likes 21mo
Half-life determines how quickly concentration approaches steady state and does not determine what the steady-state concentration is. Dose and clearance determine that.
0 likes 21mo
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
Happy to be the one who is wrong here if it settles the question.
28 likes 21mo
LJankowiak, post #32: Building on post #29 rather than restating it. 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. Go to post
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.
I would rather be precise about what I do not know than vague about what I do.
Post #103 is the version of this I will quote in future. One addition.
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.
The literature is thinner on this than the confidence in the thread implies.
2 likes 21mo
Collapsed as off-topic by two members at trust level 3 or above
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.
The number is defensible. The precision I gave it is not.
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.
Reporting the observation and leaving the explanation open deliberately.
0 likes 21mo
Nicolaides, post #22: 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
Post #103 put the caveat in the right place and I want to underline it.
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.
a.wikstrom, post #105: 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. The number is defensible. The precision I gave it is not. Go to post
Appreciated. The plain phrasing does more work here than a longer post would.
vial_desk, post #47: 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. Go to post
Picking up post #107: that is the part I would want checked first.
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.
Fair, and the limits you put on it are the part I will remember.
1 like 21mo
t.tulloch, post #42: 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
Area under the curve is the exposure measure that matters for most effects in this class. Peak concentration matters more for tolerability.
I would put the burden of proof on the interesting explanation, not the dull one.
This follows post #110 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.
21 likes 21mo
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.
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.
That is the honest state of it as of this week.
3 likes 21mo
r.coelho, post #94: Picking up post #91: that is the part I would want checked first. 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. Adding the caveat now so it does not have to be… 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.
Marking that as an opinion rather than a finding.
Post #116 and I disagree about the size of the effect, not about the direction.
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.
That is what the documentation says. What happens in practice is usually close.
30 likes 21mo
The arithmetic in post #118 is right; the assumption feeding it is the part to check.
Renal clearance: these compounds are cleared partly via the kidney. In severe renal impairment, clearance is slowed and accumulation risk is higher. Dose adjustments might be needed.
5 likes 21mo