Abstract
Favipiravir (T705; 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a pyrazine analog that has demonstrated potent antiviral activity against a broad spectrum of viruses in multiple in vivo disease models. To better understand the compounds anti-viral activity, assessment of the drug’s biodistribution and kinetics in vivo may lend insight into how best to evaluate the compound efficacy preclinically and to contribute to the design of clinical studies to take into account the compound’s pharmacokinetic distribution and kinetics. In the current study, a method for synthesis of [18F]favipiravir was developed and the biodistribution in mice naïve to and pre-dosed with favipiravir was assessed by PET and gamma counting of tissue samples. Fluorine-18 labeling of favipiravir was achieved in a one-pot, two-step synthesis using a commercially available precursor, methyl-5-chloroisoxazolo[4,5-b]pyrazine-3-carboxylate, with an overall radiochemical yield of 15–24%, a molar activity of 37–74 GBq/µmol in a 70 minute synthesis time. [18F]favipiravir tissue uptake and distribution was similar in naïve and pre-dosed mice; however, in the pre-dosed animals plasma clearance was more rapid and tissue clearance appeared to be prolonged. In conclusion, application of PET to the evaluation of favipiravir has demonstrated the importance of dosing regimen on the distribution and tissue uptake and clearance of the molecule. Favipiravir is cleared through the kidney as previously reported but the liver and intestinal excretion may also play an important role in compound elimination. Measurement of the tissue uptake of favipiravir as determined by PET may be a more important indicator of a compound’s potential efficacy than purely monitoring plasma parameters such as viremia and drug levels.
Highlights
Of 125–400 mg/kg orally followed by daily maintenance doses of 75–200 mg/kg orally while not having an effect on overall survival in Ebola infected non-human primates was shown to increase time to death and reduce plasma viremia[9]
Since clinical dosing of favipiravir required a loading dose followed by a maintenance dose, we evaluated the distribution of [18F] favipiravir in mice naïve to favipiravir and after 7 doses of favipiravir
The authors selected the dosing regimen based on modeling of pharmacokinetic data which predicted stable plasma drug levels; the clinical data indicated that after 4 days of dosing plasma drug levels were lower than calculated by the model
Summary
Of 125–400 mg/kg orally followed by daily maintenance doses of 75–200 mg/kg orally while not having an effect on overall survival in Ebola infected non-human primates was shown to increase time to death and reduce plasma viremia[9]. The JIKI trial which treated Ebola-infected patients with favipiravir utilized a loading dose of 6000 mg on day 1 followed by a maintenance dose of 1200 mg twice daily for the remainder of the study[10]. Given that the study was only able to demonstrate changes in plasma levels following treatment, we hypothesized that a loading dose of favipiravir would result in different distribution patterns of the drug and that PET would allow us to detect the differences dynamically
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