Ibuzatrelvir (PF-07817883): A Comprehensive Profile of a Second-Generation Oral Antiviral for the Treatment of COVID-19

Executive Summary

Ibuzatrelvir, also known by its development code PF-07817883, is an investigational, orally bioavailable antiviral agent developed by Pfizer as a second-generation therapeutic for the treatment of COVID-19.[1] It is classified as a small molecule inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), an enzyme essential for viral replication. The primary strategic rationale behind its development is to improve upon the clinical limitations of its predecessor, nirmatrelvir, the active antiviral component of the combination therapy Paxlovid.[1]

The mechanism of action of ibuzatrelvir involves a reversible covalent interaction between its nitrile "warhead" and the active site cysteine residue (Cys145) of the viral 3C-like (3CL) protease.[1] This interaction effectively blocks the enzyme's ability to cleave viral polyproteins, thereby halting the viral replication cycle. A key design feature of ibuzatrelvir is its improved metabolic stability compared to nirmatrelvir. This enhancement obviates the need for co-administration with a pharmacokinetic booster like ritonavir, which is a potent inhibitor of the cytochrome P450 3A (CYP3A) enzyme system.[3] By eliminating ritonavir from the regimen, ibuzatrelvir is designed to have a significantly lower potential for the drug-drug interactions (DDIs) that currently limit the use of Paxlovid in patients with complex comorbidities and concomitant medications.