title: Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial.
abstract: Celgosivir (6-O-butanoyl castanospermine), a pro-drug of the naturally occurring castanospermine, is an inhibitor of α-glucosidase I and II that is found to be a potent inhibitor of several enveloped viruses including all four serotypes of dengue virus. We showed previously that the compound fully protected AG129 mice from lethal infection with a mouse adapted dengue virus at a dose of 50mg/kg twice daily (BID) for 5days and was effective even after 48h delayed treatment. Here we show that the protection by celgosivir is dose- and schedule-dependent and that a twice-a-day regimen of 50, 25 or 10mg/kg is more protective than a single daily dose of 100mg/kg. Treatment with 50mg/kg BID castanospermine had comparable efficacy as 25mg/kg BID celgosivir, suggesting that celgosivir is approximately twice as potent as castanospermine with respect to in vivo antiviral efficacy. Pharmacokinetics (PK) studies of celgosivir in mice showed that it rapidly metabolized to castanospermine. Simulation of the PK data with the survival data for the various doses of celgosivir tested suggests that the steady-state minimum concentration is a critical parameter to note in choosing dose and schedule. These results influenced the selection of the dose regimen for a proof-of-concept clinical trial of celgosivir as a treatment against dengue fever.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 16985, Singapore.
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Abhay P S
authors.initials: AP
authors.lastname: Rathore
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sung
authors.forename: Fan
authors.initials: F
authors.lastname: Lu
authors.forename: Yok Moi
authors.initials: YM
authors.lastname: Khoo
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.forename: Jenny
authors.initials: J
authors.lastname: Low
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.forename: How Sung
authors.initials: HS
authors.lastname: Lee
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004358:Drug Therapy / Q000379:methods; D007212:Indolizines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D016019:Survival Analysis; D054836:Indolizidines
chemical_list: D000998:Antiviral Agents; D007212:Indolizines; C070715:celgosivir; D054836:Indolizidines; C037806:castanospermine