Bioequivalence and Bioavailability Forum

Hi Dan,

nice that you post again.

❝ if the recommended dosage regimen of the IR as per product monograph IR is to be given every 4 hrs then this means that higher doses have either a safety issue or the dose/effect relationship is in disfavor of higher doses. In this case AUC alone does not matter. Consequently, a regulatory body will reject the study

I disagree. John was asking for ER (once a day) vs. IR (twice a day with τ 4 hours). In Europe that’s a hybrid application (dunno the US term; 505(b)2?). Quite common, if no ER exists and should be development for various reasons (better compliance, convenience for the patient).
Say the single IR doses are 10 mg and the ER 20 mg. It might well be that the originator’s IR is approved for up to 40 mg given a single doses.¹
In the comparison AUC is primary. Whether the first/second peak of the ER has to match the C_max-values of the IR administrations (and to which degree) is another story. I have seen assessing both but with expanded limits, non-superiority² (to assess potential dose-dumping), only the global C_max, and even just a descriptive analysis. Which one is the right approach depends on the drug, of course.

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1. Real example. Don’t ask me for the drug.
   
2. Preferred in the EMA’s MR-GL (together with non-inferiority of C_τ = the bracketing approach). See an example in the vignette of PowerTOST.