ABSTRACT
In the last years, several studies on new and/or repurposing antiviral drugs were initiated to fight Coronavirus disease 2019 (COVID-19) pandemic. Three antivirals have so far been authorised in Italy for the treatment of COVID-19 in adults who do not need supplemental oxygen and who are at high risk of progressing to severe COVID-19. Specifically, the drugs currently authorized are Remdesivir (intravenous route) and the orally administered Molnupiravir and Nirmatrelvir-Ritonavir (Paxlovid). Remdesivir is a prodrug of the nucleotide analogue (GS-441524) which inhibits the SARS-CoV-2 RNA-dependent RNA polymerase. Remdesivir has been shown to improve the COVID-19 outcome in different settings. Molnupiravir is a prodrug that after entering in the cells changes into an active form of triphosphate, ready to be incorporated into viral genome causing many errors in SARS-CoV-2 RNA. In a clinical trial, Molnupiravir compared to placebo showed a 30% reduction of COVID-19-related hospitalizations. Paxlovid is a combination of Nirmatrelvir and Ritonavir. Nirmatrelvir acts by inhibiting protease enzyme, essential step to transform some viral proteins into their final functional form. The relative risk reduction of hospitalization or all-cause death at day 28 for Paxlovid compared to placebo was 88%. To guarantee safe and effectiveness of the pharmacological therapies, the evaluation of patient's pharmacokinetics (PK) profile is mandatory. Therefore, the monitoring of drug concentration of antivirals against SARS-CoV2 could be pivotal to optimise drug regimens, increase efficacy and avoid drug-related toxicity and to evaluate intra-individual variability and drug-drug interactions. Actually, few data on antiviral drugs concentrations in COVID-19 subjects are published. Among them, the most interesting are the following: i) Remdesivir and its main metabolite showed high PK interpatient variability due to both age and renal function in COVID-19 inpatients. The PK variability may have a potential effect in determining the efficacy of Remdesivir administration in patients affected by COVID-19. ii) Molnupiravir metabolite penetration into upper airways and mucosal secretions was demostred. These data could support the use of molnupiravir in a prophylaxis for SARS-CoV-2 infection iii) Nirmatrelvir displays a short half-life, which could result in suboptimal drug exposure and difficulties in achieving efficacy. Therefore, there is the need to use ritonavir (CYP3A4 Inhibitor) to slow down the metabolism and to increase the plasma concentrations of Nirmetrelvir. Drug-drug interactions are expected when drugs metabolized by CYP3A4 are co-administered with Paxlovid. Further research on antiviral drugs concentrations in COVID-19 patients could help to define therapeutic strategies more efficient and appropriate to treat SARSCoV-2 infection.