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

Saken Khaidarov1*, Bayan Nurgaliyeva2*, Aibek Yermekbay3, Abzal Maratov4, Venera Abdulla5 and Saule Kariyeva2

1Department of Molecular Biology and Medical Genetics, Asfendiyarov Kazakh National Medical University, Zheltoksan 37A Street, Almaty 050012, Kazakhstan
2*Department of Propaedeutics of Internal Medicine, Asfendiyarov Kazakh National Medical University, Tole-bi Street 94, Almaty, 050012, Kazakhstan
3Department of Anesthesiology and Resuscitation, Asfendiyarov Kazakh National Medical University, Tole-bi Street 94, Almaty, 050012, Kazakhstan
4FIZTEX, Ladygina 35 A, 050000, Almaty, Kazakhstan
5Kazakh Academy of Sports and Tourism (KazAST), Abay Street 83/85, Almaty 050022, Kazakhstan.

Received: 11th Sep, 2025; Revised: 25th Oct 2025; Accepted: 8th Nov, 2025; Available Online: 1st December, 2025

ABSTRACT

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. Favipiravir, 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. Isobologram 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.

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

How to cite this article: Khaidarov S, Nurgaliyeva B, Yermekbay A, Maratov A, Abdulla V and Kariyeva S; Synergistic Inhibition of Sars-Cov-2 By Favipiravir and Ribavirin: Quantitative CI/DRI Analysis and Therapeutic Implications. Int J Drug Deliv Technol. 2026;16(1): 403-420. DOI: 10.25258/ijddt.16.1.43