Analysis of Nirmatrelvir Entry into Pulmonary Lining Fluid in Patients with COVID‐19: A Unique Perspective to Explore and Understand the Target Plasma Concentration of 292 ng/mL in Antiviral Activity

ABSTRACT Background Currently, the applicant has chosen a target plasma trough concentration for nirmatrelvir, which is adjusted to 292 ng/mL based on the drug's molecular weight (499.54 Daltons), its binding to human plasma proteins (69%), and the in vitro antiviral EC90 value (181 nM). However, the current exposure‐effect relationships (ER) analysis of viral load in patients enrolled in the EPIC‐HR study has not revealed clinically significant trends in the ER. Given that the lungs are the primary site of COVID‐19 infection, we aim to further understand this exposure relationship by exploring and analyzing the penetration characteristics of nirmatrelvir in the lungs. Objectives To explore and understand the target plasma concentration of 292 ng/mL in antiviral activity. Methods We identified all critically ill patients with coronavirus disease 2019 who received nirmatrelvir/ritonavir treatment in the respiratory intensive care unit of Changhai hospital between January 2023 and October 2023. Samples of plasma and bronchoalveolar lavage fluid were obtained at pre‐dose trough concentrations after administration of nirmatrelvir (NMV). The relationship between NMV levels in plasma and the epithelial lining fluid (ELF) was assessed by determining concentrations of NMV. Results There was a significant relationship between NMV levels in plasma and ELF (ELF = 0.4976*PLASMA‐ 204; R = 0.96), with a correlation whose slope (0.4976) suggested that the blood‐to‐ELF ratio of drug penetration was 2:1. A negative value from the equation indicates that NMV requires to reach baseline concentration to penetrate the ELF. Conclusions The relationship between NMV levels in plasma and ELF with low permeability and a negative baseline value suggests that the target plasma concentration of 292 ng/mL is insufficient for antiviral activity. This study provides a unique perspective to explore and understand no clinically meaningful trend of exposure‐response relationships in patients enrolled in EPIC‐HR. This study is the first to explore nirmatrelvir penetrating human epithelial lining fluid from the blood. We assessed the relationship between nirmatrelvir levels in plasma and those in human epithelial lining fluid to elucidate that the currently applied nirmatrelvir target plasma exposure of EC90 value (292 ng/mL) is not adequate for patients.