Bioequivalence and Bioavailability Forum

Hi mittyri,

❝ ❝ If t_½ of active metabolite > t_½ of parent, assess only the metabolite.

❝

❝ Could you please explain a little bit? When did I miss that good old times?

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 (t_½ ~16 h) and its main metabolite nortriptyline (t_½ >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.


^{© 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?

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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.