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Health Canada Guidance

2. Overview. Certainly a generally thoughtful review, but I'm not sure how much guidance it provides.I.Pre-clinical in vitroIt ought to focus on the type II lesions (unpredictable, dose and time-independent and (to date) rarely seen in animals. 3. I.Pre-clinical in vitro. It asserts that there

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Health Canada Guidance

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    1. Health Canada Guidance Robert J. Temple, M.D. Associate Director for Medical Policy Center for Drug Evaluation and Research U.S. Food and Drug Administration

    2. 2 Overview Certainly a generally thoughtful review, but I’m not sure how much guidance it provides. I. Pre-clinical in vitro It ought to focus on the type II lesions (unpredictable, dose and time-independent and (to date) rarely seen in animals

    3. 3 I. Pre-clinical in vitro It asserts that there is dose-dependency – not so clear I think (except APAP) They say reactive metabolites (current hypothesis) serve as haptens, cause pathogenic immune response – is there evidence for this, or are metabolites directly toxic? Why would immune response target the liver particularly? Also, put forth “danger hypothesis,” i.e., that “the body” creates an immune response to “danger,” not “foreignness,” e.g., to direct cell damage (but then why do you need an immune response to explain anything). Certainly APAP is not immune-mediated

    4. 4 I. Pre-clinical in vitro If we want to test hypotheses we need a list of all idiosyncratic hepatotoxins and either see what animal data showed or do new studies. They should provide one isoniazide trovafloxacin iproniazid parhexilene bromfenac nefazadone alclofenac ticrynafen ibufenac felbamate diclofenac dantrolene troglitizone tolcapone labetalol valproate dilevalol etc.

    5. 5 I. Pre-clinical in vitro They suggest screen for active metabolites using glutathione and looking for conjugates. But do we know whether this picks up most/all the known hepatotoxins? And are there false positives? (Not a word about this in the report) Also suggest screen for covalent binding. Again, what do we know about whether that picks up heptatoxins?

    6. 6 I. Pre-clinical in vitro Suggest metabolites react to inhibit P450, inactivating the enzyme irreversibly (I don’t know if this is so, but I doubt it) and, as for ticrynafen “lead to an immune response against P450, which causes hepatic necrosis.” Is this documented at all? Why would immune response to P450 lead to necrosis? Many of the drugs on the list are not significant P450 inhibitors. In sum, if there are any data to support any of the recommended maneuvers, none are cited.

    7. 7 II. Pre-clinical in vivo Re type II hepatotoxicity, is there evidence that Tier I studies are of any value? Without some discussion of relation to “the list,” this is not helpful. Tier II studies: tests of mitochondrial tox may indeed predict FIAU-like effects, but no help re the usual hepatotoxins Tier III studies. It is not clear that any of the suggestions are of value.

    8. 8 II. Pre-clinical in vivo Unmentioned is the possibility of studying drugs in SH depleted animals, a test that does show APAP toxicity. Has such testing ever been done for any of the drugs on the list? I’ve asked and it does not appear that this has ever been tried.

    9. 9 III. Clinical The discussion of the value of the pre-clinical data overstates the value for type II lesions, which, to my best knowledge, is zero. What is not conveyed well is the array of possible clinical signals and what they mean

    10. 10 III. Clinical What is needed is a review of the specificity and sensitivity of possible signals of hepatocellular injury. Candidates are: A greater frequency of TA elevations to 3X ULN in the treatment compared to control group An increased rate (vs. control) of 5X, 10X, etc. elevations. These can be informative even without a control.

    11. 11 III. Clinical 3. Even a few (2) Hy’s Law cases, meaning TA elevation, usually substantial Increased bilirubin to 2X ULN (or maybe baseline) No significant obstruction (AP elevation or evidence of GB disease, cancer, etc.) History says the rate of serious injury will be roughly 10% of the rate of Hy’s law cases. The rate of these cases in an untreated population is very low (Senior data on large placebo group) if you make sure to capture all of the underlying diseases

    12. 12 III. Clinical Hy’s Law cases were seen with bromfenac, dilevalol, troglitizone and are easy to spot with INH, iproniazid, dantrolene. They did not occur with tolcapone or nefazadone, but the rate of severe injury with those drugs is low, so that a larger safety data base would have been needed. Certainly, we (still) need to closely examine the known hepatotoxins and non-hepatotoxins to establish the S+S of the tests.

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