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).