Bioequivalence and Bioavailability Forum

What is clinically relevant? [Design Issues]

posted by Helmut  – Vienna, Austria, 2018-04-06 22:05 (1296 d 06:48 ago) – Posting: # 18649
Views: 4,766

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 Le Chatelier’s principle and is simply driven out from the liposomes due to the concentration gradient (C_liposomes > C_blood).

—
Dif-tor heh smusma 🖖
Helmut Schütz


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Complete thread:

• Counterintuitive? nobody 2018-04-03 11:16 [Design Issues] 
  • Counterintuitive? bebac_fan 2018-04-03 18:20
    • Counterintuitive? nobody 2018-04-03 23:25
      • Counterintuitive? bebac_fan 2018-04-04 00:43
        • Counterintuitive? nobody 2018-04-04 11:03
    • What is clinically relevant? Helmut 2018-04-04 16:49
      • What is clinically relevant? nobody 2018-04-05 10:04
      • What is clinically relevant? bebac_fan 2018-04-05 14:19
        • What is clinically relevant? nobody 2018-04-06 09:22
        • What is clinically relevant? Helmut 2018-04-06 16:10
          • What is clinically relevant? bebac_fan 2018-04-06 20:53
            • What is clinically relevant?Helmut 2018-04-06 22:05
              • Korsmeyer–Peppas’ model mittyri 2018-04-06 23:36