Counterintuitive? [Design Issues]

posted by bebac_fan – US, 2018-04-03 20:20 (2077 d 20:32 ago) – Posting: # 18635
Views: 5,653

Hi Nobody,

❝ Why should the most appropriate AUC metric depend on the release rate of the Test product relative to reference? Any ideas how to wrap my head around this?

I'll take a shot. I am a clinical pharmacologist, so forgive me if I am not speaking the language. I am happy to clarify.

This is regarding a liposomal formulation that has funky kinetics.

A mix of liposomal-bound and free doxorubicin is infused, then some liposomal-bound slowly leaches out (they call this rate REL). Different liposomal formulations can introduce considerable variance in RES, it is reasonable to check out how to detect bad liposomal formulations using unbound + total PK doxorubicin PK samples.

Looking at the model, REL is much smaller than clearance. This is "flip flop kinetics," where the rate and extent of absorption aren't adequately covered by Cmax and AUC. SQ Biologics usually have this - insulins, MABs, etc. In flip flop kinetics, Cmax usually corresponds to the clearance of the drug, and terminal t 1/2 corresponds to the absorption rate - quite opposite to what we're used to.

So given the funky kinetics, the authors simulated a "what if" scenario by changing the RES and saw what NCA parameters were best at identifying it.

If the liposomal formulations leached more quickly (E.g. RELt > RELr), the drug would switch from flip-flop kinetics to standard kinetics.

Attached is an image showing how PK changes shape greatly when changing REL.


Hope this helps -

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