Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice.
Antiviral Res
; 208: 105430, 2022 Dec.
Article
in English
| MEDLINE | ID: covidwho-2060394
ABSTRACT
As the SARS-CoV-2 pandemic remains uncontrolled owing to the continuous emergence of variants of concern, there is an immediate need to implement the most effective antiviral treatment strategies, especially for risk groups. Here, we evaluated the therapeutic potency of nirmatrelvir, remdesivir and molnupiravir, and their combinations in SARS-CoV-2 infected K18-hACE2 transgenic mice. Systemic treatment of mice with each drug (20 mg/kg) resulted in slightly enhanced antiviral efficacy and yielded an increased life expectancy of only about 20-40% survival. However, combination therapy with nirmatrelvir (20 mg/kg) and molnupiravir (20 mg/kg) in lethally infected mice showed profound inhibition of SARS-CoV-2 replication in both the lung and brain and synergistically improved survival rates up to 80% compared to those with nirmatrelvir (36%, P < 0.001) and molnupiravir (43%, P < 0.001) administered alone. This combination therapy effectively reduced clinical severity score, virus-induced tissue damage, and viral distribution compared to those in animals treated with these monotherapies. Furthermore, all these assessments associated with this combination were also significantly higher than that of mice receiving remdesivir monotherapy (P < 0.001) and the nirmatrelvir (20 mg/kg) and remdesivir (20 mg/kg) combination (P < 0.001), underscored the clinical significance of this combination. By contrast, the nirmatrelvir and remdesivir combination showed less antiviral efficacy, with lower survival compared to nirmatrelvir monotherapy due to the insufficient plasma exposure of the remdesivir, demonstrating the inefficient therapeutic effect of this combination in the mouse model. The combination therapy with nirmatrelvir and molnupiravir contributes to alleviated morbidity and mortality, which can serve as a basis for the design of clinical studies of this combination in the treatment of COVID-19 patients.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
SARS-CoV-2
/
COVID-19 Drug Treatment
Type of study:
Experimental Studies
/
Prognostic study
/
Randomized controlled trials
Topics:
Variants
Limits:
Animals
Language:
English
Journal:
Antiviral Res
Year:
2022
Document Type:
Article
Affiliation country:
J.antiviral.2022.105430
Similar
MEDLINE
...
LILACS
LIS