Bioequivalence and Bioavailability Forum

Dear Hari,

please no questions to me personally, but to the group.

❝ I have gone through a draft guidance issued by FDA suggesting that the study sholud be carried out in patients using mercaptopurine.

You are talking about this one?
5-MP is known to be genotoxic and potentially carcinogenic.

❝ I wolud like to know whether the draft guidence was finalised and published …

As of today not a single one of all individual BE guidances has been finalized.

❝ … and what it says …

FDA essentially suggests a steady-state study in patients, strength 50 mg (individual therapeutic dosages), analyte 5-MP. Although not given verbatim, a parallel design can be assumed (due to progression of the disease and irreversible binding of the active metabolites to erythrocytes).

5-MP is a nasty compound: an inactive pro-drug, highly variable (CV >50%), diurnal variable (night/day 167%), non-linear PK, interactions with methotrexate (150%).
Of the three major metabolic pathways two lead to inactive compounds (thiopurine methyl transferase → 6-methyl-MP, xanthinoxidase → 6-thioxanthine).
The FDA’s document contains a comment, that ‘patients with inherited deficiency of the enzyme thiopurine methyl transferase must be excluded from these studies.’ This is a hint of the parallel design (because in a cross-over this would not matter).
In some regimens allopurinol is co-administered to block xanthinoxidase; such patients should also be excluded (following the FDA’s logic, because this is the other metabolic pathway).

❝ … and can we carry out the study in healthy subjets.

Before talking any further, please answer these two questions:

• would you attend in such a study yourself?
  
• would you suggest your children attending in such a study?

If both answers are “yes” we can talk about the first one again.

Dear Hari,
If the FDA recommendation states to do the study with patients means that there is an safety issue in conducting the study with healthy subjects, so as per guidance you have to go.
Regards

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Edit: Full quote removed. Please see this post! [Jaime]