Simulation framework [NCA / SHAM]

posted by Helmut Homepage – Vienna, Austria, 2019-04-17 13:31  – Posting: # 20183
Views: 1,812

Hi mittyri,

» » If t½ of active metabolite > t½ of parent, assess only the metabolite.
»
» Could you please explain a little bit? When did I miss that good old times?

[image]This was the standard approach till the mid 1990s.1,2,3
The idea behind was clinical relevance. An example often discussed at that time was amitriptyline (t½ ~16 h) and its main metabolite nortriptyline (t½ >30 h). Both are about equally potent. In steady state (you never ever administer a single dose of a tricyclic antidepressant) the metabolite causes >⅔ of the effect. Which one is more relevant?
Tucker even argued that in a linear system any compound with the lowest variability (parent, active or inactive metabolite) could be chosen. Hence, for a while he was called Geoff “pick-out-the-best” Tucker in the community.
Already at the Bio-International in 1994 the pendulum started to swing towards the approach we are now bound to.4 Since its frequency is low and its amplitude high we will have to wait a good while till it turns. :-(

BTW, proceedings of the Bio-International conferences make still a great read and help in understanding how – and why – we ended up here.

[image] © Tomas Salmonson
Maybe you can get the first ones used. If you find the third covering the Bio-International 1996 in Yokohama somewhere let me know. I lost mine…

» ready for simulation:

I corrected a typo in your original post from

» SubjectsDFstack <-
    reshape(SubjectsDF[, -c(2,3,4,6,7,9,11)],
      direction = 'long', varying = 3:5, v.names = "ratio", timevar = "metric", times = names(SubjectsDF1)[3:5])


to

SubjectsDFstack <-
  reshape(SubjectsDF[, -c(2,3,4,6,7,9,11)],
    direction = 'long', varying = 3:5, v.names = "ratio", timevar = "metric", times = names(SubjectsDF)[3:5])


So what do you conclude?


  1. Importance of Metabolites in Assessment of Bioequivalence. In: Midha KK, Blume HH, editors. Bio-International. Bioavailability, Bioequivalence and Pharmacokinetics. Stuttgart; medpharm: 1993. p. 147–208.
  2. Blume HH, Midha KK. Bio-International ’92, Conference on Bioavailability, Bioequivalence and Pharmacokinetic Studies. Pharm Res.1993;10(12):1806–11. doi:10.1023/A:1018998803920.
  3. Tucker GT. Bioequivalence – A Measure of Therapeutic Equivalence? In: Blume HH, Midha KK, editors. Bio-International 2. Bioavailability, Bioequivalence and Pharmacokinetic Studies. Stuttgart; medpharm: 1995. p. 35–43.
  4. Welling PG. Bioequivalence – A Measure of Quality Control? In: Blume HH, Midha KK, editors. Bio-International 2. Bioavailability, Bioequivalence and Pharmacokinetic Studies. Stuttgart; medpharm: 1995. p. 45–49.

Cheers,
Helmut Schütz
[image]

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