What is clinically relevant? [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2018-04-06 18:10 (2264 d 23:17 ago) – Posting: # 18647
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Hi BF,

❝ […] in practice, "trauma" from the peristaltic IV pump and the narrow gauge needle can release drug.

Hhm, never thought about that! Though I didn’t see an early “release” in one of my studies: Example Caelyx (50 mg/m2: 72.2 – 109.4 mg), length of infusion 01:17 – 01:53 hours, LLOQ 18 µg/mL (encapsulated doxorubicin: left), 9 ng/mL (free: right).

[image]  [image]

❝ However, it is very cool to hear that this may be an artifact!

Cool, maybe. Nasty if you want to assess the PK. Below one subject where obviously sumfink went wrong in sample handling at the clinical site (analytical result confirmed from the backup sample).



What the heck? The concentration of free doxorubin at 25.5 h is ~25 (!) times the two adjacent concentrations. Since the metabolite is formed from the parent in plasma, it’s clear that we face an artifact.

❝ ❝ IMHO, encapsulated, free, and total doxorubicin are not relevant from a clinical perspective – only nice to know.

❝ I agree. I believe the free is only clinically relevant.

From a clinical perspective, yes. Given the crazy results I faced in some cases, the metabolite would be more robust – though we would have to sample substantially longer in order to get a reliable estimate of the AUC.

❝ Imposing tests on the bound form is like measuring the amount of drug in the gut (i.e. the "liposome") and in the blood (i.e. unbound in blood).


❝ I am not sure what I would do if I found that total had a much different PK profile, but resulted in same free fractions. Probably explode.


❝ […] I have not found any other forum even tangentially related to clinical pharmacology, pharmacometrics, or drug development that is anywhere as active.

❝ Thanks for the great discussion.

Thanks from my side as well!

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