Peak-to-trough ratio at steady state for a weekly agent posts 31–60

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.

post #46 answers the question as asked. The question underneath it is different.

Thank you for the correction. I have edited my earlier post with a note rather than silently, so the thread still makes sense to read. The error was mine and it was the kind that comes from remembering a figure instead of looking it up.

On post #44 — agreed on the reasoning, with one qualification.

Hepatic metabolism: the degree to which each compound is hepatically metabolised versus renally cleared is known but varies. Severe liver disease changes clearance.

This follows post #46 rather than contradicting it.

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 read post #48 twice before replying, because I had assumed the opposite.

Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing.

The correction was fair and I had been repeating something I had not checked carefully enough.

Worth separating two things that post #47 runs together.

Albumin binding: semaglutide binds albumin through a fatty side chain, which sequesters the free form and extends the half-life. Tirzepatide also has albumin binding (different mechanism) which extends its half-life compared to an unmodified peptide.

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.

SNAC (the oral bioavailability enhancer): sodium N-(8-[2-hydroxybenzoyl]amino) caprylate transiently raises gastric pH and promotes absorption. Without it, oral bioavailability is too low for clinical use. With it, bioavailability is still variable between people.

This follows post #51 rather than contradicting it.

Thank you for the correction. I have edited my earlier post with a note rather than silently, so the thread still makes sense to read. The error was mine and it was the kind that comes from remembering a figure instead of looking it up.

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.

Hepatic metabolism: the degree to which each compound is hepatically metabolised versus renally cleared is known but varies. Severe liver disease changes clearance.

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.

Picking up post #55: that is the part I would want checked first.

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.

Worth separating two things that post #55 runs together.

Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing.

The correction was fair and I had been repeating something I had not checked carefully enough.

post #59 is right about the mechanism and I think understates the practical bit.

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.