Rowland, T. | bioRxiv Science

bioRxiv2026

Dose optimisation of favipiravir against RNA viruses using physiologically-based pharmacokinetic modelling.

Favipiravir (FPV) is an RdRp inhibitor developed and licensed in Japan for influenza but which has shown promising in-vitro activity against a range of RNA viruses. A physiologically-based pharmacokinetic model was developed for oral FPV and its metabolite M1 in order to optimise the dose regimen against plasma concentration targets for a number of viral pathogens. The model was validated using clinical data and was able to capture the variability in plasma concentrations for a population of individuals. FPV doses predicted to cause in-vivo exposures exceeding in-vitro IC90 targets against influenza, Ebola, Lassa fever, CCHF, SFTS, Andes virus and SARS-CoV-2, lie within the window of observed safe dosing, with SARS-CoV-2 requiring predicted doses of 2400 mg twice daily due to lower in-vitro potency. Simulations showed that a loading dose on day one of treatment should allow plasma targets to be exceeded on day one. Simulations of chronic kidney disease (CKD) showed no change to FPV plasma concentration in individuals with CKD3 and CKD5 compared to healthy individuals. Clinical data suggested active renal efflux of M1 which led to a predicted 2.2 and 11.5 fold increase in the maximum plasma concentrations of M1 in individuals with CKD3 and CKD5 respectively in comparison with healthy individuals.

pharmacology and toxicology↗

bioRxiv2019

Single-cell imaging reveals unexpected heterogeneity of TERT expression across cancer cell lines

Telomerase is pathologically reactivated in most human cancers, where it maintains chromosomal telomeres and allows immortalization. Because telomerase reverse transcriptase (TERT) is usually the limiting component for telomerase activation, numerous studies have measured TERT mRNA levels in populations of cells or in tissues. However, little is known about TERT expression at the single-cell and single-molecule level. Here we analyzed TERT expression across 10 human cancer lines using single-molecule RNA FISH and made several unexpected findings. First, there was substantial cell-to-cell variation in number of transcription sites and ratio of transcription sites to gene copies. Second, previous classification of lines as having monoallelic or biallelic TERT expression was found to be inadequate for capturing the TERT gene expression patterns. Finally, TERT mRNA had primarily nuclear localization in cancer cells and induced pluripotent stem cells (iPSCs), in stark contrast to the expectation that mature mRNA should be predominantly cytoplasmic. These data reveal unappreciated heterogeneity, complexity, and unconventionality in TERT expression across human cancer cells.

cancer biology↗