To determine the tolerance of HIV-infected patients to TID oral doses of FIAU syrup at 4 different dose levels. To determine the peak and trough blood levels of FIAU and its metabolites during two weeks of oral dosing with FIAU.
The pyrimidine nucleoside analog FIAC and its primary deaminated uracil metabolite FIAU are highly and specifically active compounds in vitro against several herpes group viruses, particularly herpes simplex virus (HSV) types 1 and 2, varicella zoster (VZV), and cytomegalovirus (CMV), as well as hepatitis B virus (HBV). Since FIAU is the primary metabolite of FIAC and the administration of FIAU simplifies the metabolism of FIAC, it is anticipated from clinical studies of FIAC that FIAU will be tolerated at least as well as FIAC. A single-dose, pharmacokinetic (blood level) study showed that FIAC, when taken orally, is readily absorbed into the bloodstream, and most of it is converted to FIAU. Daily oral doses are expected to provide concentrations of FIAU exceeding the in vitro minimum inhibitory concentration for nearly all the herpes group viruses.

Start Date-

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

[+1]

100 Clinical Results associated with Fialuridine

100 Translational Medicine associated with Fialuridine

100 Patents (Medical) associated with Fialuridine

103

Literatures (Medical) associated with Fialuridine

01 Jan 2024·Toxicology Research

A mechanistic biomarker investigation of fialuridine hepatotoxicity using the chimeric TK-NOG Hu-liver mouse model and in vitro micropatterned hepatocyte cocultures

Article

Author: Glaab, Warren E ; Xu, Qiuwei ; Muniappa, Nagaraja ; Lebron, Jose ; Pacchione, Stephen ; Tracy, Rodger William ; Erdos, Zoltan ; Galijatovic-Idrizbegovic, Alema ; Lane, Pamela ; Aslamkhan, Amy G ; Sistare, Frank D ; Ohnishi, Yasuyuki ; Wang, Zhibin ; Koeplinger, Kenneth ; Podtelezhnikov, Alexei ; Liu, Liping ; Vlasakova, Katerina ; Michna, Laura ; Valentine, John ; Suemizu, Hiroshi ; Kuhls, Matthew C

AbstractFialuridine (FIAU) is a nucleoside-based drug that caused liver failure and deaths in a human clinical trial that were not predicted by nonclinical safety studies. A recent report concluded that a TK-NOG humanized liver (hu-liver) mouse model detected human-specific FIAU liver toxicity, and broader use of that model could improve drug safety testing. We further evaluated this model at similar dose levels to assess FIAU sensitivity and potential mechanistic biomarkers. Although we were unable to reproduce the marked acute liver toxicity with two separate studies (including one with a “sensitized” donor), we identified molecular biomarkers reflecting the early stages of FIAU mitochondrial toxicity, which were not seen with its stereoisomer (FIRU). Dose dependent FIAU-induced changes in hu-liver mice included more pronounced reductions in mitochondrial to nuclear DNA (mtDNA/nucDNA) ratios in human hepatocytes compared to mouse hepatocytes and kidneys of the same animals. FIAU treatment also triggered a p53 transcriptional response and opposing changes in transcripts of nuclear- and mitochondrial-encoded mitochondrial proteins. The time dependent accumulation of FIAU into mtDNA is consistent with the ≥9-week latency of liver toxicity observed for FIAU in the clinic. Similar changes were observed in an in vitro micro-patterned hepatocyte coculture system. In addition, FIAU-dependent mtDNA/nucDNA ratio and transcriptional alterations, especially reductions in mitochondrially encoded transcripts, were seen in livers of non-engrafted TK-NOG and CD-1 mice dosed for a shorter period.Conclusion: These mechanistic biomarker findings can be leveraged in an in vitro model and in a more routine preclinical model (CD-1 mice) to identify nucleosides with such a FIAU-like mitochondrial toxicity mechanistic liability potential. Further optimization of the TK-NOG hu-liver mouse model is necessary before broader adoption for drug safety testing.

01 Oct 2023·Clinical Pharmacology & Therapeutics

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Review

Author: Wright, Stephen H. ; Hau, Raymond K. ; Cherrington, Nathan J.

The US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidances on small‐molecule drug–drug interactions (DDIs), with input from the International Transporter Consortium (ITC), recommend the evaluation of nine drug transporters. Although other clinically relevant drug uptake and efflux transporters have been discussed in ITC white papers, they have been excluded from further recommendation by the ITC and are not included in current regulatory guidances. These include the ubiquitously expressed equilibrative nucleoside transporters (ENT) 1 and ENT2, which have been recognized by the ITC for their potential role in clinically relevant nucleoside analog drug interactions for patients with cancer. Although there is comparatively limited clinical evidence supporting their role in DDI risk or other adverse drug reactions (ADRs) compared with the nine highlighted transporters, several in vitro and in vivo studies have identified ENT interactions with non‐nucleoside/non‐nucleotide drugs, in addition to nucleoside/nucleotide analogs. Some noteworthy examples of compounds that interact with ENTs include cannabidiol and selected protein kinase inhibitors, as well as the nucleoside analogs remdesivir, EIDD‐1931, gemcitabine, and fialuridine. Consequently, DDIs involving the ENTs may be responsible for therapeutic inefficacy or off‐target toxicity. Evidence suggests that ENT1 and ENT2 should be considered as transporters potentially involved in clinically relevant DDIs and ADRs, thereby warranting further investigation and regulatory consideration.

01 May 2023·Journal of Hepatology

A human liver organoid screening platform for DILI risk prediction

Article

Author: O'Meara, Matthew J ; Fontana, Robert J ; Capeling, Meghan M ; Childs, Charlie J ; Huang, Sha ; Meyer, Sophia R ; Zhang, Charles J ; Spence, Jason R ; Sexton, Jonathan Z ; Ferrer-Torres, Daysha

BACKGROUND & AIMSDrug-induced liver injury (DILI), both intrinsic and idiosyncratic, causes frequent morbidity, mortality, clinical trial failures and post-approval withdrawal. This suggests an unmet need for improved in vitro models for DILI risk prediction that can account for diverse host genetics and other clinical factors. In this study, we evaluated the utility of human liver organoids (HLOs) for high-throughput DILI risk prediction and in an organ-on-chip system.METHODSHLOs were derived from three separate iPSC lines and benchmarked on two platforms for their ability to model in vitro liver function and identify hepatotoxic compounds using biochemical assays for albumin, ALT, AST, microscopy-based morphological profiling, and single-cell transcriptomics: i) HLOs dispersed in 384-well-formatted plates and exposed to a library of compounds; ii) HLOs adapted to a liver-on-chip system.RESULTSDispersed HLOs derived from the three iPSC lines had similar DILI predictive capacity as intact HLOs in a high-throughput screening format, allowing for measurable IC₅₀ values of compound cytotoxicity. Distinct morphological differences were observed in cells treated with drugs exerting differing mechanisms of toxicity. On-chip HLOs significantly increased albumin production, CYP450 expression, and ALT/AST release when treated with known hepatoxic drugs compared to dispersed HLOs and primary human hepatocytes. On-chip HLOs were able to predict the synergistic hepatotoxicity of tenofovir-inarigivir and displayed steatosis and mitochondrial perturbation, via phenotypic and transcriptomic analysis, on exposure to fialuridine and acetaminophen, respectively.CONCLUSIONSThe high-throughput and liver-on-chip systems exhibit enhanced in vivo-like functions and demonstrate the potential utility of these platforms for DILI risk assessment. Tenofovir-inarigivr-associated hepatotoxicity was observed and correlates with the clinical manifestation of DILI observed in patients.IMPACT AND IMPLICATIONSIdiosyncratic (spontaneous, patient-specific) drug-induced liver injury (DILI) is difficult to study due to the lack of liver models that function as human liver tissue and are adaptable for large-scale drug screening. Human liver organoids grown from patient stem cells respond to known DILI-causing drugs in both a high-throughput and on a physiological "chip" culture system. These platforms show promise for researchers in their use as predictive models for novel drugs before entering clinical trials and as a potential in vitro diagnostic tool. Our findings support further development of patient-derived liver organoid lines and their use in the context of DILI research.

100 Deals associated with Fialuridine

External Link

KEGG	Wiki	ATC	Drug Bank
D04181	Fialuridine	-	DB15427

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B	Phase 2	-	National Institutes of Health	-
Hepatitis B	Phase 2	-	Allergan Ltd. (Ireland)	-
Hepatitis B	Phase 2	-	Allergan Ltd. (Ireland)	-
Hepatitis B	Phase 2	-	National Institutes of Health	-

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