Thanks. The following is by way of background, for me and others.
(I see there was a .2% vs .1% increase in the bilirubin signal in ARISE.)
fda.gov
Certain laboratory assessments are so critical to the safety assessment that they deserve special attention in any review. For example, hepatotoxicity has been an important cause of drug marketing withdrawals from the 1950s (iproniazid) to the present (ticrynafen, benoxaprofen, troglitizone, bromfenac) and has led to important limitations on the use of many more drugs (isoniazid, labetalol, trovafloxacin, tolcapone, nefazodone, felbamate). At present, it appears that a potential for severe hepatotoxicity may be signaled by a set of findings sometimes called Hy's Law, based on the observation by Hy Zimmerman, a major scholar of drug-induced liver injury, that a pure hepatocellular injury leading to jaundice had serious implications, a 10 to 50 percent mortality. Over the years, this observation has led to the following proposition:
In a drug development database, a potential for severe hepatotoxicity is signaled by the following set of findings:
1. An increased rate of transaminase elevations (3x ULN, 5x ULN, 10x ULN, etc.) in treated patients compared to control
2. No significant evidence of obstruction (elevated AP), although some elevation may follow severe hepatocellular injury
3. A very small number of cases (two, perhaps even one) of transaminase elevation accompanied by a rise in bilirubin to 2x ULN
The explanation for the usefulness of this signal is the high capacity of the liver for bilirubin excretion; it takes a good deal of damage to the liver to impair bilirubin excretion (in the absence of obstruction). This signal has been present for troglitizone, bromfenac, and dilevalol (never approved in the United States, but hepatotoxic in Portugal).
Table 7.1.7.5.1 is an outline of a comprehensive assessment of available data pertinent to potential hepatotoxicity.
<snip>
<from the referenced chart...>
III. Possible problems/signals
A. Any patient with elevated transaminase (to at least 3x ULN, generally higher), no evidence of obstruction (elevated AP) and even modestly (2X ULN) elevated bilirubin. Greater elevation of bilirubin is stronger signal.
B. Greater rate than control of 3x, 5x, 10x, etc. elevations of transamisne. |
