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Hepatic Failure and Lactic Acidosis Due to Fialuridine (FIAU), an Investigational Nucleoside Analogue for Chronic Hepatitis B
Open accessAbstract
BACKGROUND: We describe severe and unexpected multisystem toxicity that occurred during a study of the antiviral nucleoside analogue fialuridine (1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil, or FIAU) as therapy for chronic hepatitis B virus infection. METHODS: Fifteen patients with chronic hepatitis B were randomly assigned to receive fialuridine at a dose of either 0.10 or 0.25 mg per kilogram of body weight per day for 24 weeks and were monitored every 1 to 2 weeks by means of a physical examination, blood tests, and testing for hepatitis B virus markers. RESULTS: During the 13th week lactic acidosis and liver failure suddenly developed in one patient. The study was terminated on an emergency basis, and all treatment with fialuridine was discontinued. Seven patients were found to have severe hepatotoxicity, with progressive lactic acidosis, worsening jaundice, and deteriorating hepatic synthetic function despite the discontinuation of fialuridine. Three other patients had mild hepatotoxicity. Several patients also had pancreatitis, neuropathy, or myopathy. Of the seven patients with severe hepatotoxicity, five died and two survived after liver transplantation. Histologic analysis of liver tissue revealed marked accumulation of microvesicular and macrovesicular fat, with minimal necrosis of hepatocytes or architectural changes. Electron microscopy showed abnormal mitochondria and the accumulation of fat in hepatocytes. CONCLUSIONS: In patients with chronic hepatitis B, treatment with fialuridine induced a severe toxic reaction characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy. This toxic reaction was probably caused by widespread mitochondrial damage and may occur infrequently with other nucleoside analogues.
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“Fialuridine (Section 7.1) and troglitazone (Section 7.4) are intrinsic toxicodynamic failures, driven by human-relevant mitochondrial injury and reactive-metabolite formation, respectively.”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [69]
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“Fialuridine, an antiviral nucleoside analogue, caused catastrophic hepatic failure and lactic acidosis in a 1993 clinical trial, resulting in five deaths and two liver transplantations.”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [69]
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“Preclinical studies across multiple species showed no indication of the severe mitochondrial toxicity observed in humans, because fialuridine’s incorporation into mitochondrial DNA is mediated by a human-specific mitochondrial transporter [69,70].”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [69]
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“Fourth, idiosyncratic toxicities, such as those underlying the fialuridine and troglitazone failures, are by definition not captured by any pharmacokinetic scaling framework, and even sophisticated PBPK or PBPK–PD models cannot reliably anticipate them without orthogonal mechanistic assays [69,70,75,76].”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [69]
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“even sophisticated PBPK or PBPK–PD models cannot reliably anticipate them without orthogonal mechanistic assays [69,70,75,76]”
From Beyond Body Weight: A Comprehensive Review of Allometric Scaling in Drug Development for Human Dose Predictions (2026) · cites this paper as [69]
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“Even a pilot study on 43 patients treated for 2 and 4 weeks duration with Fialuridine did not reveal any signs of hepatic toxicity on initial examination.[17]”
From TGN1412: From Discovery to Disaster (2010) · cites this paper as [17]
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“During 13th week of phase II studies, one of the patients suddenly developed hepatic toxicity and lactic acidosis. At this point, trial was stopped for all other patients.”
From TGN1412: From Discovery to Disaster (2010) · cites this paper as [17]
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“Even after discontinuation of Fialuridine administration, seven other patients showed signs of severe hepatic toxicity five of which could not survive and other two could survive only after liver transplantation.[17]”
From TGN1412: From Discovery to Disaster (2010) · cites this paper as [17]
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Metadata
- Authors
- McKenzie, R., Fried, M. W., Sallie, R., Conjeevaram, H., Di Bisceglie, A. M., Park, Y., Savarese, B., Kleiner, D., Tsokos, M., Luciano, C., Pruett, T., Stotka, J. L., Straus, S. E., & Hoofnagle, J. H.
- Affiliations
- National Institutes of Health (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- National Institute of Allergy and Infectious Diseases (US)
- National Cancer Institute (UA)
- University of Virginia Hospital (US)
- Eli Lilly (United States) (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1995-10-26
- Volume
- 333
- Issue
- 17
- Pages
- 1099-1105
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2327070670
- Cited by
- 616
- References
- 39
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 17 · 2023: 13 · 2022: 11 · 2021: 19 · 2020: 13 · 2019: 26 · 2018: 32 · 2017: 23 · 2016: 27 · 2015: 16 · 2014: 12 · 2013: 16 · 2012: 10
- FWCI
- 28.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- NIH Clinical Center
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Keywords
- FIAU, lactic acidosis, liver failure, hepatotoxicity, chronic hepatitis B, nucleoside analogues, drug toxicity, mitochondrial damage, pancreatitis, neuropathy, myopathy, liver transplantation, drug-induced liver injury
- MeSH terms
- Acidosis, Lactic, Adult, Alanine Transaminase, Antiviral Agents, Arabinofuranosyluracil, Chronic Disease, DNA, Mitochondrial, DNA, Viral, Female, Hepatitis B, Humans, Jaundice, Liver, Male, Middle Aged, Pancreatitis, Peripheral Nervous System Diseases, Drugs, Investigational, Liver Transplantation, Liver Failure
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