Accelerating the Development of Biomarkers for Drug Safety Workshop Summary (2009) / Chapter Skim
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5 Biomarkers of Acute Idiosyncratic Hepatocellular Injury in Clinical Trials
5 Biomarkers of Acute Idiosyncratic Hepatocellular Injury in Clinical Trials
Pages 42-57
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From page 42... ...
, the population incidence of drug-induced liver injury is unknown. Yet drugs are the most frequent cause of acute liver failure among those under consideration for liver transplantation in the United States (Lee, 2003)
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From page 43... ...
and bilirubin. As a prerequisite for approval, the company was told to conduct a new safety study of 10,000 patients treated with the drug for 1 year, and to include an additional 10,000 subjects receiving comparator treatment for 1 year to exclude an unacceptable level of risk for clinically serious acute idiosyncratic hepatocellular injury (AIHI)
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From page 44... ...
100.0 start stop died Liver Test Values, xULRR 10.0 ALTx TBLx ASTx ALPx 1.0 probably drug-induced hosp 0.1 –30 0 30 60 90 120 150 180 Study Day FIGuRE 5-1 Acute idiosyncratic hepatocellular injury. An 80-year-old man who experienced acute idiosyncratic hepatocellular injury exhibited marked increases in alanine aminotransferase (ALT)
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From page 45... ...
Even frequent and fairly high ALT elevations do not reliably predict the potential to cause AIHI in clinical trials, as evidenced by tacrine. In clinical trials, about 25 percent of Alzheimer's disease patients receiving tacrine developed ALT elevations of greater than three times ULN, and 2 percent exhibited ALT elevations of greater than 20 times ULN (Watkins et al., 1994)
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From page 46... ...
However, data to support this theory are sparse. It has been claimed that with drugs capable of causing AIHI, such as isoniazid, troglitazone, and ximelagatran, the AIHI events typically occur with a latency similar to that of the more frequent ALT elevations observed in clinical trials (personal communication, D
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From page 47... ...
there should be evidence that the drug causes more frequent but less severe hepatocellular injury as shown by more frequent ALT elevations of greater than three times ULN in the treated group relative to the control group (FDA, 2007)
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From page 48... ...
The ideal biomarker also would be able to make this distinction in a relatively small clinical trial of short duration. The plausibility of such a biomarker rests on the mechanistic differences between drugs that have the potential to cause AIHI and those that cause only reversible ALT elevations.
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From page 49... ...
. Because mitochondrial damage, oxidative stress, or depletion of intracellular glutathione may be downstream of molecule-specific events, such as reactive metabolite accumulation, a drug capable of causing severe AIHI could induce characteristic changes in the serum proteome or metabolome or in the urinary metabolome that would not be present in patients treated with drugs incapable of causing AIHI.
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From page 50... ...
. It is possible that biomarkers of immune activation could be useful in distinguishing benign ALT elevations from those that can portend AIHI.
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From page 51... ...
In addition, analysis of blood/urine samples obtained in clinical trials of drugs known to cause AIHI may be useful in identifying biomarkers, especially when compared with blood/urine samples obtained in clinical trials of drugs that cause ALT elevations but do not have the potential to cause AIHI. A large prospective trial in isoniazid-treated patients has been proposed for this purpose (Watkins et al., 2008)
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From page 52... ...
HIGHLIGHTS OF THE bREAkOuT DISCuSSION In plenary session, John Bloom of Eli Lilly presented the main conclusions of participants in the breakout session on biomarkers for liver toxicity. Discussants in the breakout session observed that candidate AIHI biomarkers are best identified and validated in three relevant human populations: Hy's Law cases; subjects in prospective, controlled clinical trials with established and well-characterized AIHI agents, including isoniazid;
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From page 53... ...
Developing and Implementing Protocols for Specimen and Data Collection in Clinical Trials of Specific Marketed Drugs known to Either Cause or Not Cause AIHI A second priority is to develop and implement protocols for specimen and data collection in prospective clinical trials of isoniazid and other drugs known to cause AIHI or known to cause ALT elevations but not AIHI. A number of key questions need to be addressed.
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From page 54... ...
How can the risk for the sponsor be managed in such a situation? Making use of Existing Databases A fourth priority is to conduct a thorough examination of existing FDA liver safety databases from Phase III clinical trials, and perhaps from the Adverse Event Reporting System database, to test hypotheses for the more frequent benign ALT elevations.
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1999. Accuracy of hepatic adverse drug reaction reporting in one English health region.
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2002. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver.
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From page 57... ...
2008. Using con trolled clinical trials to learn more about acute drug-induced liver injury.
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