AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Adaptation to liver injury: tacrine, isoniazid, ethanol, experimental drugs
John R. Senior, MD
Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science,
Food and Drug Administration
Adaptation to liver injury: Tacrine, isoniazid, ethanol, experimental drugs [PDF]
Animal toxicologic studies have been generally successful in detecting conventionally toxic drug candidates and preventing them from being used clinically, but have sometimes failed to detect drugs that are injurious to only a few patients out of many, after drug approval and marketing. This has been attributed to idiosyncrasy, a misunderstood term referring to human individual differences that make some people more susceptible to drug-induced injury that is unpredictable, not dose-related, often but not always rare, and for which the mechanism of injury is unknown. Another aspect of idiosyncracy not hitherto clearly recognized has been differing capacities of diverse individuals to respond to injury by resistance, repair, regeneration, and healing of injury with restoration of normal hepatic function and subsequent tolerance to the xenobiotic substance that caused the initial injury. The liver is the principal organ that copes with effects of hundreds of endogenous and exogenous chemical substances simultaneously, and has evolved mechanisms for preserving itself while doing so; it is an amazingly robust organ. We focus our attention this afternoon upon some of these resistance-repair-regeneration processes in seeking to understand better their diversity, and how we may learn to use these mechanisms of adaptive tolerance development We are considering 21st-century material; Hy Zimmerman’s 1999 book does not even mention adaptation or tolerance. Yet some of the speakers have been working on concepts related to these phenomena for two decades.
I shall start with some clinical remarks on evidence of adaptive tolerance for some quite old compounds: ethanol, isoniazid, tacrine, and then mention some newer investigational drugs that are teaching us lessons. Ethanol is oxidized in the liver, mainly, to acetaldehyde, a very reactive compound but one that is further oxidized to acetate. Not all heavy drinkers are susceptible to serious liver injury, to develop acute hepatitis and eventually cirrhosis after many recurrent bouts following addictive repeated exposures. Most alcohol consumers either are not injured seriously, or adapt and become relatively tolerant, but only 15-20% do not and become increasingly unable to repair the damages done by the recurring bouts of acute alcoholic hepatitis. With isoniazid, even more of the users show adaptive tolerance. Even though perhaps 15-20% may show initial injury, by transaminase rises, most of them adapt, and only about 1:1000 fail to adapt and may be seriously injured. With tacrine, although about 50% of users show initial transaminase rises, the occurrence of subsequent serious injury is exceedingly rare. Each drug seems to have its own pattern or incidence of initial injury, and its own propensity to adaptive tolerance. Newer drugs also show some of these patterns, about which we are just beginning to learn.
Our ultimate aim is to be able to recognize individual patients who may be either so susceptible or so unable to resist and repair injury that they should not be exposed to a given drug and some alternative treatment used for them. We need to understand in what way they may be different from the great majority who can either tolerate the drug initially or adapt to it and then become tolerant. If so, perhaps we can devise probes or tests to identify them, or characterize risk factors that make them very likely to have trouble with the drug. We need to move beyond seeking serious drug-induced injuries that have already occurred, to predicting highly likely injuries that might occur and preventing them by excluding those few individuals from being exposed
John Senior was educated in chemical engineering at Drexel University, in physics at the Pennsylvania State University, and medicine at the University of Pennsylvania. After internal medicine residency program and a clinical fellowship in gastroenterology at the Hospital of the University of Pennsylvania, he worked on the mechanisms of intestinal absorption of fats across the small intestinal epithelial cells into the lymph and blood at the Massachusetts General Hospital and Harvard University. Returning to Penn, he established a Gastrointestinal Research Laboratory at the Philadelphia General Hospital (PGH), and there worked on detecting viral hepatitis after transfusion of blood. That hospital was the first in the world to screen all donor blood for the marker ("Australia antigen") of hepatitis B. He was elected to the council of the American Association for the Study of Liver Diseases, and was its 24th President in 1973-4.
On sabbatical from PGH, he investigated the possibilities of computer simulation of patients for purposes of testing candidates for certification of medical competence by the American Board of Internal Medicine, and developed the first models of tests that are currently are in use as the Computer-Based Examination. At the Graduate Hospital he directed its Clinical Research Center and later opened a Special Treatment Unit for Alcohol-Related Disorders at Graduate Hospital that provided advanced medical care for over 3500 patients admitted with life-threatening medical complications of alcohol abuse, referred from the Philadelphia area.
He then worked in corporate pharmaceutical research and development, at Squibb as Director of Regulatory Projects (1979-81), at Sterling-Winthrop Research Institute as Vice President for Worldwide Clinical Affairs (1981-4), and as an independent consultant to numerous pharmaceutical companies in Japan, Europe, and North America (1984-95). In June 1995 he joined the Center for Drug Evaluation and Research of the Food and Drug Administration as a medical reviewer for gastrointestinal drug products, in January 2000 as Senior Scientific Advisor to the Director of the Office of Drug Safety, consulting on drug-associated liver problems to the reviewing divisions and conducting research on detecting and attributing causality for idiosyncratic drug-induced liver injury, and July 2003 as Associate Director for Science, Office of Pharmacoepidemiology and Statistical Sciences, and is the principal hepatology consultant for the FDA.