Bioequivalence and Bioavailability Forum

Dear D. Labes!

❝ How would you describe these three profiles?

• Each with their own PK metrics (AUC, Cmax, tmax and what ever else)?
  
• Overall AUC, Cmax, tmax?
  
• Both?

❝ If we take the first or last option and it comes to the statistical evaluation we have the burden to show bioequivalence for at least 3x more parameters than usual.

❝ Or can we restrict the bioequivalence decision to lets say profile 1?

❝ And see the other profiles only as secondary?

I love your challenges! I would say it depends on the clinical impact (i.e., is drug dependent and not primarily a statistical question). If the important effect is within the day - and the evening dose is only administered to maintain steady state - I would see the first profile as the primary target. For bid antiasthmatics the evening dose should be more important.
If nothing particular in terms of effect is documented for the drug, I use a pragmatic approach: 24 h values (primary, confirmatory) for BE + values of individual profiles (secondary, descriptive). But it's evident that the global C_max (and even more t_max) is some kind of apples-and-oranges-comparison! Imagine a situation where t_max is two hours post dose. At bid we may end up with a median of 8 h...

❝ I remember a study with Aescin (12 h dosing interval),

Ha, Aescin, nasty! You've been another victim.

❝ ... with a marked difference between the morning and evening profiles.

❝ Much lower concentrations in the second profile, but also much more variable in Cmax / Cmin there.

❝ Using the metrics of each profile we were able to show equivalence for the first profile but not for the second with respect to Cmax.

❝ PTF was beyond good and evil (CV very much higher than 30%).

So what was your primary target in that study? I would say that the high variability of %PTF in that study was bad luck. In my experience as an aggregate metric it 'behaves' quite nicely in most cases.

❝ Bioequivalent?

Hhm.