What is clinically relevant? [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2018-04-06 22:05 (1296 d 06:48 ago) – Posting: # 18649
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Hi BF,

» I believe the spaghetti plots you posted are actually indicative of a infusion of unbound drug.
»
» Release of the encapsulated form follows first order kinetics and is Sequential - kind of like metabolic clearance from parent --> metabolite.

Did you notice the different concentrations scales (encapsulated doxorubicin: µg/mL, free: ng/mL)? On the average free is less than 1% of encapsulated. With just three sampling times during infusion I would say it is not possible to separate zero order (encapsulated) from first order (release from the liposomes).

» Luckily, you also posted the parent/metabolite curve for doxorubinol. Because of similarity in process, if no free drug is infused, bound and unbound PK should follow the same general shape we see in parent + metabolite.

What do you mean by bound + unbound? Encapsulated and free?

» The fact that total + free dox concentrations are colinear is pretty strong evidence for co-infusion of bound + unbound.

I still don’t think so. The release can be quite quick. Hence, the shapes looks similar but the concentrations of free doxo are always pretty low compared to encapsulated doxo.

» Further, the fact that there isn't a lag time in unbound, as well as a nonlinear shape, is evidence, too.

Again, I would contradict that. I don’t expect a lag-time. I would rather say that doxo follows [image] Le Chatelier’s principle and is simply driven out from the liposomes due to the concentration gradient (Cliposomes > Cblood).

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Helmut Schütz
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