2. Aerosolized antiviral drugs
Inhalation is the preferred route of administration for many drugs that
have a direct effect on the airways, particularly in conditions such as
asthma and chronic obstructive pulmonary disease COPD (Berger, 2009).
The inhalation route is also used to facilitate systemic administration
in other pathologies (e.g., to avoid daily insulin injections). The
major advantage of the inhalation route is the administration of the
drug to the airways in doses that are effective and have a direct action
on the site but with a much lower risk of systemic side effects. The
size of the particles administered by inhalation is of critical
importance in determining the deposit site within the respiratory tract.
The optimal size for airway deposition is 2-5 µm of mass median
aerodynamic diameter (MMAD). Larger particles tend to settle in the
upper airways, and smaller particles remain suspended and then exhaled
(Sturton et al. 2008).
There are numerous ways of administering inhaled drugs (Virchow et al.
2008):
• pressurized metred inhalers
• expansion chambers
• powder inhalers
• nebulizers
• gas
Some data have suggested the use of aerosolization in antiviral therapy
or anti-symptomatic treatment, and this is confirmed by some trials
recently registered for COVID-19 treatment.
Debs et al. (1988) conducted in vivo studies examining the effect of
oral of aerosol administration of the antiviral agent ganciclovir in an
experimental model of murine cytomegalovirus (MCMV) pneumonia. The
authors reported the same outcome for the two groups but suggested a
more specific inhibition of replication of MCMV in the lungs with the
aerosolized drugs. A more recent in vivo study has tested through
aerosol an experimental synthetic ligand (PUL-042) for Toll-like
receptor (TLR) 2/6 and TLR 9 in a mouse pneumonia experimental model.
The use of this aerosolized immune stimulant co-administered with
aerosolized antiviral oseltamivir has resulted in a greater rate of
survival in patients with influenza pneumonia compared to controls
(Leiva-juarez et al., 2018). The interest in this new type of inhaled
immune stimulant that targets the TLR pathway has resulted in a very
recent registration on clinicaltrial.gov of a new trial with PUL-042 to
reduce the severity COVID-19 pneumonia in SARS-CoV-2 positive patients
(ClinicalTrial.gov id: NCT04312997 and NCT04313023).
It has already been argued that aerosol delivery of antiviral drugs or
vaccines may lead to some advantages in safety and efficacy in treating
influenza (Wong et al., 2010). For antiviral drugs, the main advantage
of the inhalation route is the lack of first pass metabolism, which
leads to increased bioavailability. For example, the old drug ribavirin
(RBV) has been proposed for aerosol therapy in critical care situations,
but it is without strong recommendation and is restricted to high-risk
patients (Diot et al., 2016; Velkov et al., 2015). A recent comparative
retrospective cohort analysis has found no significative differences in
clinical outcome between oral and inhaled ribavirin therapy but a higher
cost for the aerosol therapy (Trang et al., 2018). However, the inhaled
RBV therapy combined with intravenous immunoglobulin is applied in bone
marrow transplant patients in cases of viral pneumonia because of its
poor systemic absorption, protecting against haemolytic anaemia
frequently noted after oral administration (Velkow et al., 2015).
One of the most well-known antiviral drugs, zanamivir
(Relenza®, GlaxoSmithKline), has showed a low oral
bioavailability: to solve this problem a new inhaled formulation has
been approved, and 15% of the inhaled dose reaches the lower
respiratory tract (Peng et al. 2000). A comparative clinical study has
underlined the greater effect of aerosol compared to oral oseltamivir in
reducing symptoms of influenza A or B (Kawai et al., 2008).
Even though IFN-γ is not an antiviral drug, it is helpful in the
treatment of some respiratory diseases due to its immunomodulatory
pharmacological activity. Recently, a novel nebulized formulation of
interferon gamma (IFN-γ) has been tested using special vibrating
mesh-type nebulizers. This experiment was conducted following the
regulatory standard requirements of methodologies for the assessment of
pulmonary drug delivery. Applying this new technology to a nebulizer
system has improved the delivery of this large molecule achieving
optimal bioavailability in the lower respiratory tract, while
maintaining its pharmacological activity. Aerosolized IFN-γ has been
tested in clinical trials showing great tolerability with some
improvement in the reduction of cavity lesion size and bacterial loads
(Moss et al., 2005; Condos et al., 2004; Condos et al., 1997).