Preclinical discovery and development of nirmatrelvir/ritonavir combinational therapy for the treatment of COVID-19 and the lessons learned from SARS-COV-2 variants

ABSTRACT

Introduction

Nirmatrelvir/ritonavir (Paxlovid_®) represent an oral antiviral therapy approved for the treatment of COVID-19. Extensive in vitro and in vivo studies have reported the promising activity of nirmatrelvir/ritonavir against numerous emerging viruses. This combination consists of nirmatrelvir, a protease reversible inhibitor of coronavirus 3CL^pro mainly metabolized by cytochrome P450 (CYP)3A4, and ritonavir, an inhibitor of the CYP3A isoforms that enhances the efficacy of nirmatrelvir by fixing its suboptimal pharmacokinetic properties.

Areas covered

This review comprehensively examines the efficacy of nirmatrelvir/ritonavir through rigorous analysis of in vitro and in vivo studies. Moreover, it thoroughly assesses its safety, tolerability, pharmacokinetics, and antiviral efficacy against SARS-COV-2 infection, based on the main pre-authorization randomized controlled trials.

Expert opinion

Nirmatrelvir/ritonavir has a good tolerability profile. Its administration during the early stages of mild-to-moderate COVID-19 holds potential benefits, as it can help prevent the onset of an aberrant immune response that could lead to pulmonary and extra-pulmonary complications. However, its drug – drug interactions can be a factor limiting its use, at least in populations on some chronic therapies, along with the risk of infection relapse after treatment.

KEYWORDS:

• Nirmatrelvir/ritonavir
• Paxlovid
• COVID-19
• Protease Inhibitor
• SARS-CoV-2 variants

Article highlights

• Inhibiting viral proteases can be considered a promising therapeutic strategy for many viral diseases.

• Nirmatrelvir is an antiviral drug that has been shown to be active against coronaviruses including SARS-CoV and SARS-CoV-2. It interacts with 3CLpro a strategically relevant SARS-CoV-2 protease.

• Investigations in cellular models demonstrate that nirmatrelvir is active against SARS-CoV-2, with promising effects in terms of reducing viral shedding both in vivo and in vitro.

• Nirmatrelvir is currently administered with ritonavir, a cytochrome P450 inhibitor which delays its metabolization. Unfortunately, its interaction with some drugs (e.g. anticoagulants) limits its use for the treatment of some high-risk patients.

• Nirmatrelvir/ritonavir can be considered a encouraging drug for COVID-19 treatment, but recurrence of disease can be reported in some patients due to the advent of mutations in the viral protease (3CLpro).

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.