Courtesy of yourself - the updated FDA guidance on DILI:
fda.gov
Some key highlights are:
“The drugs that have caused severe DILI in humans have not shown clear hepatoxicity in animals, generally have not shown dose-related toxicity, and, as noted, generally have caused low rates of severe injury in humans (1 in 5000 to 10,000 or less).”
“The finding of a higher rate of such elevations (AT – ALT or AST) in drug-treated subjects than in a control group is a sensitive signal of a potential to cause severe DILI, but it is not a very specific signal (meaning a lot of harmless drugs cause a large number of patients to have ALT>3xULN). A more specific signal of such potential is a higher rate of more marked peak AT elevations (10x-15x ULN), with cases of increases >1000 U/L causing increased concern.”
“Finding one Hy’s Law case in clinical trials is ominous; finding two is highly predictive of a potential for severe DILI. Clinical trials of the beta blocker dilevalol showed two such cases in about 1,000 exposures. The drug was not approved in the United States, and examination of a postmarketing study in Portugal revealed fatal liver injury. Clinical trials of tasosartan, an angiotensis II blocking agent, showed a single Hy’s Law case. The manufacturer was asked to do a large-scale safety study before the drug could be approved. The study was never conducted.”
“Virtually all severely hepatotoxic drugs show such cases (of AT>5x-20x ULN), indicating a high sensitivity for predicting severe DILI, but, again, some drugs such a tacrine and others that are not severely hepatotoxic also can cause AT elevations to this degree, so that specificity of this finding is suboptimal.” |
