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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: The way forward toward improved biomarkers

Paul B. Watkins, MD 
University of North Carolina
The way forward toward improved biomarkers [PDF]

Hepatocellular injury due to “metabolic idiosyncrasy” is the type of liver injury that has most frequently resulted in regulatory actions. Serum ALT (and AST) are sensitive markers for this form of liver injury, but lack specificity in identifying patients who would develop progressive liver injury. Combining ALT elevations with elevations in serum bilirubin (i.e. “Hy’s Law”) improves specificity in this regard. However, treatment is often discontinued in monitored clinical trials before liver injury is severe enough to cause bilirubin elevations. (i.e. current practices fail to identify all patients who would qualify for Hy’s rule had treatment been continued). A better biomarker would identify all patients who would have developed bilirubin elevations had treatment been continued. Broad application of transcriptomics, proteomics, and metabonomics to preclinical toxicity testing should identify novel biomarkers that appear early in the course of progressive liver injury, and this should generate candidate biomarkers for clinical studies. A challenge will be identifying appropriate patient populations in which to test these biomarkers. Again, it will not be easy to use most clinical trials for this purpose because early termination of therapy will prevent confident identification of patients with potential for progressive liver disease. One proposal would be to prospectively collect urine and serum specimens from people who begin treatment with isoniazid for tuberculosis prophylaxis. People currently started on INH for this purpose do not undergo routine ALT monitoring, which is only performed if the patient develops symptoms consistent with hepatitis. It should therefore be possible to obtain serial samples from patients who develop DILI that progresses to a symptomatic phase in addition to patients who develop transient asymptomatic ALT elevations. Such a sample bank and patient registry would be a valuable resource in the hunt for improved biomarkers.

Biographical Sketch

Paul Watkins is the Verne S. Caviness Distinguished Professor of Medicine and Professor of Pharmacotherapy, and the Director of the General Clinical Research Center at University of North Carolina, Chapel Hill. Dr. Watkins’ area of research has been Drug Metabolism and Disposition. He is one of the top 250 most cited authors in the field of Pharmacology for the two decades ending 2004 according to ISIhighlycited.com. He has served on many national committees, including Toxicology I Study Section of the National Institutes of Health and the Committee for the Comparative Toxicity of Naturally Occurring Carcinogens at the National Academy of Sciences
Dr. Watkins’ clinical area of interest is Drug-Induced Liver Injury, and he has consulted widely for industry and governmental agencies in this area. He is the current Chair of the Steering Committee for the Drug Induced Liver Injury Network (DILIN) funded by the National Institute for Diabetes Digestive and Kidney Diseases.