jag009
★★★

NJ,
2019-12-13 23:26

Posting: # 20973
Views: 821
 

 BE study design issue [Design Issues]

Hi everyone,

Question, if one conducted a study comparing ER to an immediate release reference but not following the recommended dosage regimen of the IR. Example, as per product monograph IR is given every 4 hrs and the new ER is given every 8 hrs, but the guy designed the pk study comparing ER vs 2xIR with both give at time 0, The design is obviously wrong (due to IR dosing regimen) but would a regulatory body reject the study (assume the study pass the BE objective which is BE needed only for auc). A pivotal study not pilot.

PS, not me! Doing some due diligence..
Thx
J
Helmut
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Vienna, Austria,
2019-12-14 00:42

@ jag009
Posting: # 20974
Views: 545
 

 1×2 ≠ 2×1

Hi John,

» The design is obviously wrong (due to IR dosing regimen) …

Yep.

» … but would a regulatory body reject the study (assume the study pass the BE objective which is BE needed only for auc).

I hope so. Imagine you have capacity-limited elimination. You would partly saturate the enzymes with the 1×2 regimen and see a higher AUC than with 2×1. Hence, the T/R-ratio will be positively biased. In an extreme case the study passes with the wrong design but would have failed with the correct one.

Cheers,
Helmut Schütz
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jag009
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NJ,
2019-12-15 19:39

@ Helmut
Posting: # 20977
Views: 488
 

 1×2 ≠ 2×1

Thanks Helmut!
J
ElMaestro
★★★

Belgium?,
2019-12-15 22:02

@ jag009
Posting: # 20978
Views: 482
 

 1×2 ≠ 2×1

Ahoj both,

while it is hard to disagree with the complex math behind "1×2 ≠ 2×1", this is nevertheless how some drugs are approved when originators shift from twice daily to once daily dosing (or the other way around; yes the latter also happens in rare cases).

Le tits now.

Best regards,
ElMaestro
Helmut
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Vienna, Austria,
2019-12-16 11:00

@ ElMaestro
Posting: # 20979
Views: 438
 

 x ◦ y = y ◦ x?

Hi ElMaestro,

» while it is hard to disagree with the complex math behind "1×2 ≠ 2×1", …

The [image] commutative law \(x\circ y=y\circ x\) holds only on the premise of strict linear pharmacokinetics.

» … this is nevertheless how some drugs are approved when originators shift from twice daily to once daily dosing, …

Sure, why not? As usual, know your drug and know your formulation. ;-)

Cheers,
Helmut Schütz
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Dr_Dan
★★  

2019-12-18 15:04

@ jag009
Posting: # 20992
Views: 327
 

 BE study design issue

Hi John
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
Hope this helps
KR
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Helmut
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2019-12-18 15:33

@ Dr_Dan
Posting: # 20994
Views: 324
 

 ER vs. IR

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 Cmax-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 Cmax, and even just a descriptive analysis. Which one is the right approach depends on the drug, of course.


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

Cheers,
Helmut Schütz
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Dr_Dan
★★  

2019-12-19 09:01

@ Helmut
Posting: # 21004
Views: 281
 

 ER vs. IR

Hi Helmut
your statement only holds true in your example with different strengths. If you have only one or the highest IR strength then my statement applies. The once daily (or 8 h) dosing of the ER formulation does not have to mimicry the performance of the multiple dosing of the IR formulation if you can show that there is a well-defined therapeutic window in terms of safety and efficacy and the rate of input is known not to influence the safety and efficacy profile or the risk for tolerance development.
KR
Dan

Kind regards and have a nice day
Dr_Dan
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