Mutagenesis in Norovirus in Response to Favipiravir Treatment

Abstract

Some changes to the conditions for approval were decided in the course of the deliberation. The revised conditions for approval are as follows:[Conditions for approval] 1. The applicant is required to conduct a pharmacokinetic study in accordance with the approved dosage and administration in Japan, and submit the study data and analysis results immediately after the completion of the study and within 1 year after the date of the marketing approval.2. The applicant is required to conduct a clinical study of the product in patients with seasonal influenza virus infection to verify the efficacy and confirm the safety, and to submit the study data and analysis results immediately after the completion of the study.3. The applicant must not manufacture the product without the request of the Minister of Health, Labour and Welfare, unless the study data and analysis results specified in the above 1 and 2 are submitted and necessary actions are taken accordingly.4. The applicant is required to establish a strict distribution management system, and take thorough safety measures in order to ensure that the product is not used in patients with seasonal influenza virus infection, even when the product is to be marketed.5. The applicant is required to take strict and proper measures in order to ensure that the product is not administered to patients unless each individual patient, who is judged to be eligible for its use, or his/her family member is informed of the efficacy and risk of the product in writing and their written informed consent is obtained prior to the start of treatment. *Japanese Accepted Name (modified INN)This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. 2.A.(1) Drug substance 2.A.(1).1) Characterization (a) General propertiesThe determined physicochemical properties of the drug substance include description, X-ray powder diffraction, solubility, hygroscopicity, melting point and thermal analysis, dissociation constant, partition coefficient, and crystalline polymorphism.The drug substance is a white to light yellow powder. It is sparingly soluble in acetonitrile and in methanol, and slightly soluble in water and in ethanol (99.5). It is slightly soluble at pH 2.0 to 5.5 and sparingly soluble at pH 5.5 to 6.1.The drug substance is not hygroscopic at 25°C/51% to 93%RH. The melting point is 187°C to 193°C, and the dissociation constant (pKa) is 5.1 due to the hydroxyl group of favipiravir. Measurement results on the partition ratio of favipiravir in water/octanol at 25°C indicate that favipiravir tends to be distributed in the 1-octanol phase at pH 2 to 4 and in the water phase at pH 5 to 13. (b) Structure determinationThe structure of the drug substance is supported by elemental analysis, ultraviolet-visible spectrophotome...

Current treatment of COVID-19 in renal patients: hope or hype?

“…The antiviral 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705, favipiravir) Favipavir (FP) is a RNA-dependent RNA polymerase (RdRp) inhibitor. Its use was approved only in Japan for the treatment of influenza infection and it is distributed only upon request by the Minister of Health, Labor and Welfare of Japan to avoid irrational prescriptions [50] In addition to its anti-influenza activity, FP blocks the replication of other RNA viruses [51]. FP has been used for the treatment of human infection with life-threatening Ebola virus and severe fever with thrombocytopenia syndrome [52].…”

Viral infection in primary antibody deficiency syndromes

“…Prolonged shedding times of norovirus have been reported by several studies in both symptomatic and apparently asymptomatic individuals with CVID. Shedding times have been reported by others as long as 1200 days with serial positive faecal samples and gastrointestinal biopsies, while we have recently described a patient infected with the US95/96 strain of norovirus (which circulated until 2002) who was still excreting virus in 2017 . Of particular interest in this regard is the potential association of norovirus with “CVID enteropathy.” This term has been used to describe various pathological entities in CVID patients with diarrhoea, including nonspecific colitis or inflammation resembling classical inflammatory bowel disease.…”

“…Paradoxically, other groups have reported clinical response to anti‐TNF therapies and steroids, although histological response to these therapies has not been documented . Recently, we have treated a patient with the novel antiviral favipiravir and observed marked changes in the dominant viral haplotype as well as accelerated mutagenesis in minority variants, coinciding with clinical response . Another potential treatment under evaluation is nitazoxanide, currently being formally evaluated in post‐stem cell transplant patients in the United States .…”

2’-Fluoro-2’-deoxycytidine inhibits murine norovirus replication and synergizes MPA, ribavirin and T705

“…Despite their wide clinical application, the potential side effects or unintended off-target effects of nucleoside analogues should be considered. Induction of mutagenesis by T705 treatment in patients has raised questions for treating chronic norovirus infections [18]. Previous studies have reported that 2'-FdC exhibits delayed toxicity after prolonged exposure, and no adverse clinical effects were observed in rats and woodchucks after 90 days of treatment [20].…”

“…Favipiravir, also known as T-705, has been approved for the treatment of influenza in Japan and has been repositioned to treat patients with Ebola virus infection [16,17]. It has been shown to be effective against noroviruses, but the treatment can induce mutagenesis in mice and in patients, challenging the application of favipiravir for treating chronic norovirus infection [18].…”