3.3 Remdesivir
Remdesivir is an investigational compound that was developed for the
treatment of Ebola (Mullard, 2018; Tchesnokov, Feng, Porter, & Gotte,
2019). Remdesivir is a monophosphoramidate prodrug and acts as a
broad-spectrum antiviral that can be incorporated into viral RNA
(Agostini et al., 2018; Sheahan, Sims, Leist, Schafer, et al., 2020; T.
K. Warren et al., 2016). Many anti-virals are proving to be ineffective
against COVID-19 due to the presence of a proofreading exoribonuclease
(ExoN) specific to coronaviruses, encoded in non-structural protein 14
(nsp14) (Agostini et al., 2018). Remdesivir is able to evade this viral
proofreading, meaning its incorporation into viral RNA results in the
inhibition of RNA-dependent RNA polymerases (RdRps), thereby preventing
subsequent viral replication (Travis K. Warren et al., 2016).
Furthermore, Arshad et al. suggest that the maximum serum concentration
(Cmax) of remdesivir is sufficient to inhibit 90 % of
SARS-CoV-2 replication, a parameter which is suspected to be of vital
importance in the treatment of COVID-19 (Arshad et al., 2020).
Remdesivir is administered intravenously, with single doses ranging
between 3 to 225 mg being well tolerated in Ebola patients (n = 8)
(Clinical Trials.gov, 2019). Similar observations were made in the
blinded, placebo-controlled multiple-dose studies, during which Ebola
patients (n = 8) received an intravenous infusion of 150 mg remdesivir
daily for either 7 or 14 days; only grade 1 and 2 adverse reactions were
reported (Clinical Trials.gov, 2019). The proposed dosing regimen for
COVID-19 patients receiving remdesivir via the UK Early Access to
Medicines Scheme (EAMS) is similar to that which was evaluated for Ebola
treatment: a loading dose of 200 mg on day 1, followed by 100 mg daily
for 5 - 10 days depending on symptom severity (Medicines and Healthcare
products Regulatory Agency, 2020b). As such, it is likely that many of
the AEs observed in the Ebola study will translate to COVID-19 patients
treated with remdesivir.
Mild to moderate ALT and aspartate transaminase (AST) elevations were
observed in several Ebola patients during the multiple-dose study, thus
reflecting observations made in human hepatocytes in vitro(Clinical Trials.gov, 2019; World Health Organisation, 2018). This is
likely to be due to the high cell permeability of hepatocytes, in
combination with the effective intracellular metabolism of remdesivir to
its active form within the liver (World Health Organisation, 2018).
Emerging data has suggested that SARS-CoV-2 may target ACE2 on
hepatocytes leading to liver injury as evidenced by a significant
increase in ALT and bilirubin in severe cases of COVID-19 (Guan et al.,
2020). Therefore, it is likely that differentiating between
COVID-19-induced transaminase elevations and those induced by remdesivir
presents challenges (Bangash, Patel, & Parekh, 2020; C. Zhang, Shi, &
Wang, 2020). However, a recent study found that only 4.1 % of COVID-19
patients receiving remdesivir treatment suffered serious (grade 3 or 4)
transaminase elevations, with there being no significant difference
between the remdesivir- and placebo-treated groups (Beigel et al.,
2020). This data implies that remdesivir is relatively well-tolerated in
SARS-CoV-2-positive patients. Regardless, as advised by the drug
manufacturer, daily liver function tests are essential in any patients
receiving remdesivir, with suggested discontinuation of the drug in
patients whose ALT levels reach ≥ 5 times the upper limit of normal
(ULN) (Gilead, 2020). Adhering to these guidelines is of particular
importance in patients with pre-existing liver disease, or in those
taking other medications which can also induce transient ALT and AST
elevation (World Health Organisation, 2018).
The reported differences between preclinical and clinical data regarding
the safety of remdesivir highlight the inadequacies of preclinical
models in some contexts. For example, with regards to COVID-19, a
concerning element of theoretical toxicity is that which affects the
respiratory system. A study using mice models of Middle East respiratory
syndrome coronavirus (MERS-CoV) found remdesivir improved pulmonary
pathology in infected mice and rhesus monkeys, and no respiratory
toxicity was observed (Gilead, 2020; Sheahan, Sims, Leist, Schafer, et
al., 2020). In contrast, a respiratory safety study in rats showed that
remdesivir had no impact on tidal volume or minute volume, but did
increase respiratory rate, which returned to baseline by 24 hours
post-dose (World Health Organisation, 2018). Clearly, increased
respiratory rate is a manifestation of COVID-19, and there would be
problems in assessing causality if remdesivir was also likely to cause
of respiratory problems in a clinical setting. Fortunately, a recent
double-blind, randomized, placebo-controlled trial showed there to be no
significant differences in adverse respiratory events between the
remdesivir-treated and control arms (Beigel et al., 2020). In addition
to this, preclinical safety studies performed in rats and cynomolgus
monkeys suggested that the kidney was the target organ for
remdesivir-induced toxicity (Gilead, 2020). This was a significant
concern before the initial COVID-19 clinical trials, as it is known that
SARS-CoV-2 can cause acute kidney failure in severe cases (Ronco, Reis,
& Husain-Syed, 2020). However, this has not been reflected in COVID-19
clinical trials, where the presence of biomarkers indicative of renal
injury have not differed in patients treated with remdesivir compared to
those on placebo (Beigel et al., 2020; Gilead, 2020). However, due to
the inclusion of the solubility enhancer sulfobutylether β-cyclodextrin
sodium (SBECD) within remdesivir formulations, remdesivir is
contraindicated in patients with severe renal impairment (eGFR
< 30 ml/min) (European Medicines Agency, 2020).
Finally, remdesivir is not exempt from DDIs. Co-administration of
remdesivir with several antibiotics including rifampicin is
contraindicated, which could cause problems for any patients being
treated concomitantly for tuberculosis (Group, 2020). This occurs
because of enzyme induction which reduces systemic exposure to
remdesivir. A similar interaction has also been seen with
enzyme-inducing anticonvulsants, including carbamazepine, phenytoin, and
phenobarbital (Group, 2020), where reduction in remdesivir exposure may
lead to inadequate treatment of COVID-19.