3.4 Favipiravir
Favipiravir is another broad-spectrum anti-viral prodrug which undergoes intracellular phosphoribosylation to produce its active form, favipiravir-ribofuranosyl-5′-triphosphate (favipiravir-RTP) (Yousuke Furuta, Komeno, & Nakamura, 2017). It is thought that this anti-viral primarily acts by inducing lethal mutagenesis of RNA viruses, although it also selectively and potently inhibits viral RdRp by acting as a pseudo purine nucleotide (Dawes et al., 2018; Sangawa et al., 2013). Favipiravir is currently licensed in Japan for the treatment of novel and re-emerging influenza (Yousuke Furuta et al., 2013; Y. Furuta et al., 2002). Its extensive spectrum of activity against various RNA virus polymerases led to favipiravir being cited as a potentially ‘crucial pandemic tool’, even before the outbreak of the novel coronavirus, COVID-19 (Adalja & Inglesby, 2019).
The PK of favipiravir was initially characterised in healthy Japanese volunteers (Madelain et al., 2016). A Cmax of 51.5 µg/mL was found to occur 2 hours post-administration, but plasma concentrations decreased rapidly due to the relatively short half-life of favipiravir (between 2 and 5.5 hours) (Madelain et al., 2016). However, both Cmax and half-life increase slightly after multiple doses and it has been suggested that favipiravir is capable of reaching a Cmax in humans sufficient to inhibit 90 % of SARS-CoV-2 replication, thus establishing it as an important compound in the ongoing search for COVID-19 therapies (Arshad et al., 2020).
Marked differences in Cmax have been observed between Japanese and American patients with Cmax values in Japanese subjects being on average 13.26 µg/mL greater than those in American subjects (PMDA, 2014). This highlights the need for relevant COVID-19 clinical trials to include a diverse range of subjects so that factors such as weight and ethnicity can be considered to optimise dose. The bioavailability of favipiravir is high at 97.6 % and only 54 % of the drug is plasma protein-bound, suggesting high tissue penetration would be likely (Madelain et al., 2016; PMDA, 2014). In vivo work in mice showed that the half-life of favipiravir in the lungs is double that of favipiravir in plasma, indicating slower elimination from the lungs (PMDA, 2014). This is thought to be of high importance in COVID-19, where viral load is particularly high in the lungs. For influenza treatment in adults, 1600 mg favipiravir is given twice on day 1 of treatment, followed by 600 mg twice daily from days 2 to 5 (PMDA, 2014). However, the dosing period has been extended in ongoing COVID-19 clinical trials: up to 10 days in ChiCTR2000029996 and 14 days in ChiCTR2000029548 (Guan et al., 2020; ”Identifier ChiCTR2000029996, A randomized, open-label, controlled trial for the efficacy and safety of Farpiravir Tablets in the treatment of patients with novel coronavirus pneumonia (COVID-19),” 2020). It is therefore essential that all PK parameters are monitored in these trials as differences, including increased Cmax and decreased clearance, are expected during this prolonged dosing regimen which may impact upon safety.
Favipiravir has been linked to teratogenicity and embryotoxicity, and is therefore contraindicated in pregnancy (Yousuke Furuta et al., 2013). Overall, favipiravir is generally thought to have a good safety profile (Asrani, Devarbhavi, Eaton, & Kamath, 2019; Group, 2020; NHS, 2019). This is likely to be due to the fact that unlike other antiviral drugs such as ribavirin, favipiravir does not appear to disrupt non-viral RNA or DNA synthesis. However, very little is known about the long-term safety of favipiravir, as in previous clinical trials patient follow-up has been as little as 5 days (Pilkington, Pepperrell, & Hill, 2020). This is perhaps less of a concern in COVID-19 as treatment is time-limited.
Drug-drug interactions have been reported with favipiravir. For example, coadministration with favipiravir can increase exposure to paracetamol by around 15 %, which may be a concern for patients with pre-existing liver disease as paracetamol is the leading cause of acute drug-induced liver injury (DILI) in the UK and USA (Asrani et al., 2019; Group, 2020). Favipiravir can also increase patient exposure to many contraceptives, including progesterone-only pills, combined pills, and several contraceptive implants, which may cause discomfort, prolonged vaginal bleeding, and nausea (Group, 2020; NHS, 2019). Whether the increased exposure to oestrogens caused by concomitant treatment with favipiravir can enhance the risk of thrombosis is not known but should be monitored, given the overwhelming evidence that COVID-19 increases the risk of blood clots (Atallah, Mallah, & AlMahmeed, 2020; Di Micco et al., 2020; Spiezia et al.). Interestingly , large clots are most common in patients under the age of 50; almost 25 % of women aged between 15 - 49 in the USA currently use either oral or long-acting contraceptives, and thus represent a particular risk group (Hurley, 2020; Prevention, 2019).