Synergistic Inhibition of Sars-Cov-2 By Favipiravir and Ribavirin: Quantitative CI/DRI Analysis and Therapeutic Implications

Khaidarov S. Nurgaliyeva B. Yermekbay A. Maratov A. Abdulla V. Kariyeva S.
2026 Dr. Yashwant Research Labs Pvt. Ltd.

International Journal of Drug Delivery Technology
2026 #16 Issue 1 403 - 420 pp.

Combination antiviral therapy offers a rational strategy to enhance treatment efficacy and limit resistance in RNA virus infections; however, synergistic interactions must be demonstrated quantitatively rather than inferred solely from drug mechanisms. Favi-piravir, a purine analogue that induces lethal mutagenesis, and Ribavirin, a nucleoside analogue that depletes intracellular GTP pools and promotes error-prone replication, both exhibit broad activity against RNA viruses, including coronaviruses. Despite their mechanistic complementarity, the pharmacodynamic interaction between these two agents has not been rigorously defined for SARS-CoV-2. In this study, we evaluated the antiviral effects of Favipiravir and Ribavirin alone and in constant-ratio combinations using SARS-CoV-2-infected Vero E6 cells. Median-effect modelling and Chou-Talalay analysis were applied to determine the Combination Index (CI) and Dose-Reduction Index (DRI) across multiple fractional effect levels. Favipiravir and Ribavirin each demonstrated dose-dependent inhibition of viral replication, enabling accurate derivation of median-effect parameters. The 1:1 combination produced consistent synergy (CI < 1) across Fa₅₀-Fa₉₀, accompanied by favourable dose-reduction values for both drugs. The 1:2 ratio showed mild synergy, while the 2:1 ratio shifted toward additive or weakly antagonistic effects, highlighting the ratio- dependent nature of the interaction. Isobolo-gram analysis supported these observations, demonstrating deviation of experimental points below the line of additivity for synergistic combinations. These findings reveal a previously uncharacterized synergistic relationship between Favipiravir and Ribavirin against SARS-CoV-2 and provide quantitative guidance for the potential optimization of dual-nucleoside antiviral regimens. Further in vivo and pharmacokinetic studies are warranted to assess clinical relevance.

antiviral synergy , Chou-Talalay method , Combination Index (CI) , constant-ratio design , Dose-Reduction Index (DRI) , Favipiravir , IMPDH inhibition , isobologram analysis , lethal mutagenesis , nucleoside analogues , Ribavirin , SARS-CoV-2

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Department of Molecular Biology and Medical Genetics, Asfendiyarov Kazakh National Medical University, Zheltoksan 37A Street, Almaty, 050012, Kazakhstan
Department of Propaedeutics of Internal Medicine, Asfendiyarov Kazakh National Medical University, Tole-bi Street 94,, Almaty, 050012, Kazakhstan
Department of Anesthesiology and Resuscitation, Asfendiyarov Kazakh National Medical University, Tole-bi Street 94, Almaty, 050012, Kazakhstan
FIZTEX, Ladygina 35 A, Almaty, 050000, Kazakhstan
Kazakh Academy of Sports and Tourism (KazAST), Abay Street 83/85,, Almaty, 050022, Kazakhstan

Department of Molecular Biology and Medical Genetics
Department of Propaedeutics of Internal Medicine
Department of Anesthesiology and Resuscitation
FIZTEX
Kazakh Academy of Sports and Tourism (KazAST)

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