Bioequivalence and Bioavailability Forum

Hi ssussu,

❝ Should I just need to design the sampling time to 72hr or need to longer than 72hr?

❝ If I just sampling for 72hr， how can I prove the drug is a long half life drug?

In my humble opinion and experience:

• Up to 72hrs
  
• You will perhaps see some subjects do not display much of an elimination phase within the sampling time span. It is actually not easy to define quantitatively how you deliver the proof of subjects not entering the elimination phase or not doing it much. The thinking is of course that you compare AUC72 to AUCinf but since AUCinf is not always estimated due to missing elimination constants direct numerical gymnastics on AUCinf and AUC72 isn't going to be possible in all cases.
  There are generally two explanations for not having an elimination constant: Too short sampling time or a lot of scatter.
  So, depending on how long the elimination phase is you may or not have have AUCinf for some subjects. As long as you can argue it isn't a scatter issue you will then be fine for those, and for the rest it may come down to a plain comparison of the AUCs.

It is not much of a deal, actually.

Hi ssussu,

which is your “target” agency? If you want to submit the study to the (US)FDA you have to provide the protocol to the OGD for review anyway.
BTW, I never understood why the FDA allows AUC_0–72 for drugs with “low intrasubject variability in distribution and clearance” only. The latter might be possible to show based on published data (though difficult because one needs the subjects’ λ_z). The former is almost impossible without raw data and PK modeling. In BE we are interested in absorption (property of both the drug and the formulation). Distribution/elimination are solely properties of the drug. I don’t get the FDA’s rationale.

❝ If I just sampling for 72hr， how can I prove the drug is a long half life drug?

I agree with what ElMaestro wrote. You posted in the right category – that’s a design issue. Think about planing the washout. It is based on an expected half-life (literature, previous studies). No agency* asks for a demonstration that f.i. the washout was 5–10×t_½ of subjects (only that there are no residual concentrations >5% of C_max in higher periods).

It is an open question what a “long half-life drug” is. An numerous conferences both the FDA and the EMA refused to give a definition. Only the Canadian HPFB formerly stated t_½ ≥24 hours.

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• In Taiwan one has to demonstrate that the saturation phase in multiple dose studies was “sufficient”. Hence these poor guys have to sample beyond τ…