Bioequivalence and Bioavailability Forum • What is clinically relevant?

What is clinically relevant? [Design Issues]

posted by Helmut – Vienna, Austria, 2018-04-04 16:49 (1596 d 02:20 ago) – Posting: # 18641
Views: 5,329

Hi BF,

» A mix of liposomal-bound and free doxorubicin is infused, …

Are you sure? I know only liposome-encapsulated formulations (i.e., containing no free doxorubicin).

I agree that the FDA’s guidance (asking for AUC and C_max of free and liposome-encapsulated doxorubicin) might not sufficiently enough characterize the profiles.

There is no product-specific guidance in Europe so far. However, current regulatory practice on this side of the pond is much more strict.
PK metrics for encapsulated, free, and total doxorubicin:

primary: AUC_0–t, AUC_0–∞, C_max.
secondary: pAUC_0–48, pAUC_48–t. I have seen discussion with agencies when you fail on the partial AUCs.

PK metrics for the primary metabolite doxorubicinol: As above but supportive only.

Problems are manifold:

Blood samples have to be immediately put on ice and stabilized in order to prevent rupture of liposomes during centrifugation. I have seen funky “profiles” of free doxorubicin where some concentrations clearly were an artifact (the corresponding profiles of doxorubicinol were nice).
Doxorubicinol is mainly responsible for the effect.

IMHO, encapsulated and total doxorubicin are not relevant from a clinical perspective – only nice to know. I would prefer to assess just the metabolite but all of its PK metrics in a confirmatory manner.

BTW, at the 3^rd GBHI conference (Amsterdam, April 12–13) Session IV will be devoted to liposomal parenteral preparations. Let’s wait for regulators’ unfathomable wisdom.

—
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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