Idiosyncratic drug hepatotoxicity is the main cause of compound failure in Phase II drug development and post-market drug withdrawals, label changes and use restrictions.
The hallmark of idiosyncratic drug reactions is their occurrence in a unique, small proportion of individuals exposed to a drug, and much effort is focused on understanding what accounts for the uniqueness of an individual affected.
Idiosyncrasy can be allergic or non-allergic depending on the presence of clinical features such as fever, rash, eosinophilia and other symptoms related to the adaptive immune system. Tools to diagnose allergic idiosyncratic hepatotoxicity are lacking but lymphocyte-stimulation tests show promise.
Common to both types of idiosyncratic drug reaction is the occurrence of background mild liver injury, leading to the 'danger hypothesis', which suggests that a transient, mild liver injury might progress to severe drug-induced liver injury depending on genetic and environmental factors in concert with adaptive mechanisms such as inflammation and cell death.
Measurement of serum alanine transferase is a sensitive indicator of liver function used in clinical trials and could be extended to monitoring liver toxicity for drugs on the market. However, this approach suffers from poor compliance, lack of proven efficacy and the possibility of withdrawing beneficial drugs from patients at low or no risk of toxicity.
More knowledge of the clinical signatures of idiosyncratic drug reactions could help to predict hepatotoxicity in the absence of appropriate animal models, but is hindered by a lack of knowledge about the mechanisms of toxicity and the extent to which toxicity is drug-specific.
The mechanism of hepatotoxicity of acetaminophen (paracetamol) in animal models and humans is well established and could be extrapolated to provide insights into idiosyncratic toxicity in humans, particularly the role of the innate immune system and cell-death pathways.
Progress in understanding the causes of drug-induced idiosyncratic liver toxicity will require identification of specific determinants both in drug-metabolism pathways and in pathways involved in cell repair, regeneration and adaptation.
The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals. This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone). In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed. Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.
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The author thanks M. Vidrio for assistance for preparing the manuscript and National Institutes of Health grants.
N.K. is a consultant for AstraZeneca, GlaxoSmithKline, Pfizer and Sankyo, and plaintiff's expert witness in acetaminophen (paracetamol) litigation.
A small molecule that reacts with a specific antibody but which cannot induce the formation of antibodies unless bound to a carrier protein or other large antigenic molecule.
Inflammation of the liver, caused by infectious or toxic agents and characterized by jaundice, fever, liver enlargement and abdominal pain.
Stoppage or suppression of bile flow.
Bile-duct epithelial cell.
Accumulation of fat in the liver.
The presence of fat in liver cells accompanied by inflammation and fibrosis.
A type of chronic, progressive liver disease in which liver cells are replaced by scar tissue.
- PELIOSIS HEPATIS
Blood-filled spaces in the liver due to injury to endothelial cells.
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Kaplowitz, N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 4, 489–499 (2005). https://doi.org/10.1038/nrd1750
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