Hepatic impairment and the absence of data — setting out what I have, and where I think it stops being reliable.
I was wrong about hepatic impairment in a thread last spring and I would like to correct it publicly rather than quietly.
The error was in the units, which changed the conclusion by an order of magnitude. Setting out the corrected version, and the way I now check for that class of mistake.
Hepatic impairment is a question about a distribution, not about a value, and treating it as a value is what produces the confident wrong answers.
Building on post #2 rather than restating it.
A clinician's reasoning in this situation typically weighs mechanism, related-population data and the consequences of doing nothing. Naming those three makes the discussion tractable.
Answering the question post #4 raises rather than the one it answers.
Adolescent evidence exists for some compounds in this class and is a separate approval decision with its own trials rather than an extension of the adult data.
A qualification I should have led with rather than closed on.
Renal and hepatic impairment studies are usually small dedicated pharmacokinetic studies rather than outcome trials, and they answer exposure questions only.
The rule of thumb is fine; the edge cases are where it earns its keep.
Summarising the hepatic impairment thread so far, since it is long and the answer is buried: the first reply has the method, the fourth has the correction to it, and the rest is people agreeing at length.
Post #7 describes the usual case. This is about the unusual one.
Two people in this thread mean different things by hepatic impairment and are disagreeing about the definition while believing they are disagreeing about the facts. Worth pausing to define it.
Agreed on all of that, and I have nothing to add to it.
Answering the question post #11 raises rather than the one it answers.
Body weight at the extremes of the studied range affects exposure and the trials rarely reported enough to say by how much.
Post #12 is the version of this I will quote in future. One addition.
Where a population is under-studied, registry data accumulates first and is confounded by indication in ways that are hard to correct.
The absence of a reported signal in a population that was barely enrolled is not evidence about that population.
Adding the measurement that post #12 says would settle it.
Before the thread moves on from hepatic impairment — what is the sample size behind the claim? I am not being difficult; I have seen the same figure quoted from an n of four and from an n of four hundred.
Post #14 describes the usual case. This is about the unusual one.
Adding the boring version of hepatic impairment, because the interesting version keeps getting posted and the boring one is usually right.
Check the ordinary explanations, in order, and stop when one of them accounts for what you are seeing. Most of the time the second one does.
Adding a note of thanks rather than an opinion. I did not know most of that.
Being outside the studied population does not mean a treatment is unsafe. It means the usual evidence is not available and the reasoning has to be explicit.
Written from notes rather than memory, which is why the numbers are specific.
Older adults: sarcopenia risk is higher, polypharmacy is common, and the clinical trials did not enroll many people over 75. Extrapolating to very old people is extrapolating beyond the data.
If that reads as pedantic, it is, and it has saved me twice.
Post #19 describes the usual case. This is about the unusual one.
Renal impairment: the compounds are cleared renally to some degree. Dose adjustments might be needed in severe renal impairment. Consulting with a clinician familiar with renal dosing is prudent.
Written in the hope of being told what I have missed.
Confirming post #23 from a second method, which matters more than confirming it from a second person.
Older adults: sarcopenia risk is higher, polypharmacy is common, and the clinical trials did not enroll many people over 75. Extrapolating to very old people is extrapolating beyond the data.
I am reporting what happened, not recommending it.
A clinician's reasoning in this situation typically weighs mechanism, related-population data and the consequences of doing nothing. Naming those three makes the discussion tractable.
That matches what I was told, which is not the same as knowing it.
Coming back to post #23, because the follow-up matters more than the original answer.
Post-surgical populations, particularly after procedures affecting the gastrointestinal tract, interact with a delayed-emptying mechanism in ways that need specialist input.
Speaking for myself and not for anyone else who has posted here.
Post #27 is right about the mechanism and I think understates the practical bit.
I read the earlier replies on hepatic impairment twice before writing this, because I had assumed the opposite and wanted to be sure I was disagreeing with what was said rather than what I expected.