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Activation of PBMC by dengue virus infection depotentiates Balapiravir in dengue patients

Chen, Yen Liang and Abdul Ghafar, Nahdiyah and Karuna, Ratnaningrum and Fu, Yilong and Lim, Siew Pheng and Schul, Wouter and Gu, Feng and Yokokawa, Fumiaki and Wang, Gang and Cerny, Daniela and Fink, Katja and Blasco, Francesca and Shi, Pei-Yong (2014) Activation of PBMC by dengue virus infection depotentiates Balapiravir in dengue patients. Journal of Virology, 88 (3). pp. 1740-1747.

Official URL: http://jvi.asm.org/

Abstract

Background. In a recent clinical trial, Balapiravir, a prodrug of cytidine analog (R1479), failed to achieve efficacy in dengue patients, although the plasma minimum concentration of R1479 surpassed its EC50 value. Here we report experimental evidence to explain the discrepancy between the in vitro and in vivo results and its implication in drug development.
Methods. When dengue patients received Balapiravir, dengue virus infection had already been well established. EC50 values derived from cells pre-infected with dengue virus should be more reflective of therapeutic condition. A combinatory approach of biochemical, bioanalytical, and antiviral assays was used to determine such EC50 using primary human peripheral blood mononuclear cells (PBMCs; the target cells for dengue virus replication).
Findings. Potency of R1479 decreased by 125-fold when treating PBMCs pre-infected with dengue virus. The elevated EC50 is greater than the plasma trough concentration of R1479 observed in dengue patients treated with Balapiravir, and may explain efficacy failure. Mechanistically, dengue virus infection triggered PBMCs to generate cytokines which decreased the efficiency of PBMCs in converting R1479 to its triphosphate form (the active antiviral ingredient), resulting in decreased antiviral potency. In contrast to the cytidine-based R1479, the potency of an adenosine-based inhibitor of dengue virus (NITD008) was much less altered.
Interpretation. Viral infection in patients prior to treatment can significantly affect prodrug conversion to its active form. This effect varies among different nucleoside inhibitors and should be taken into account to estimate human efficacious dose when developing compounds that require host enzyme(s) conversion.

Item Type: Article
Keywords: Dengue Fever, Balapiravir, clinical trial, nucleoside analog inhibitor, cytokine release, cell activation
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10744

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