title: Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir.
abstract: In a recent clinical trial, balapiravir, a prodrug of a cytidine analog (R1479), failed to achieve efficacy (reducing viremia after treatment) in dengue patients, although the plasma trough concentration of R1479 remained above the 50% effective concentration (EC(50)). Here, we report experimental evidence to explain the discrepancy between the in vitro and in vivo results and its implication for drug development. R1479 lost its potency by 125-fold when balapiravir was used to treat primary human peripheral blood mononuclear cells (PBMCs; one of the major cells targeted for viral replication) that were preinfected with dengue virus. The elevated EC(50) was greater than the plasma trough concentration of R1479 observed in dengue patients treated with balapiravir and could possibly explain the efficacy failure. Mechanistically, dengue virus infection triggered PBMCs to generate cytokines, which decreased their efficiency of conversion of R1479 to its triphosphate form (the active antiviral ingredient), resulting in decreased antiviral potency. In contrast to the cytidine-based compound R1479, the potency of an adenosine-based inhibitor of dengue virus (NITD008) was much less affected. Taken together, our results demonstrate that viral infection in patients before treatment could significantly affect the conversion of the prodrug to its active form; such an effect should be calculated when estimating the dose efficacious for humans.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Yen-Liang
authors.initials: YL
authors.lastname: Chen
authors.forename: Nahdiyah
authors.initials: N
authors.lastname: Abdul Ghafar
authors.forename: Ratna
authors.initials: R
authors.lastname: Karuna
authors.forename: Yilong
authors.initials: Y
authors.lastname: Fu
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Lim
authors.forename: Wouter
authors.initials: W
authors.lastname: Schul
authors.forename: Feng
authors.initials: F
authors.lastname: Gu
authors.forename: Maxime
authors.initials: M
authors.lastname: Herve
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokohama
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Daniela
authors.initials: D
authors.lastname: Cerny
authors.forename: Katja
authors.initials: K
authors.lastname: Fink
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D003562:Cytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016207:Cytokines / Q000276:immunology; D003715:Dengue / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000821:virology*; D051379:Mice; D009705:Nucleosides / Q000008:administration & dosage* / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D009705:Nucleosides; D011355:Prodrugs; D003562:Cytidine; C508950:4'-azidocytidine; C530825:balapiravir