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).