title: Pharmacokinetic and pharmacodynamic modeling to determine the dose of ST-246 to protect against smallpox in humans.
abstract: Although smallpox has been eradicated, the United States government considers it a "material threat" and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the population.
authors.affiliation: SIGA Technologies, Corvallis, OR, USA.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Leeds
authors.forename: Frederique
authors.initials: F
authors.lastname: Fenneteau
authors.forename: Nathalie H
authors.initials: NH
authors.lastname: Gosselin
authors.forename: Mohamad-Samer
authors.initials: MS
authors.lastname: Mouksassi
authors.forename: Nastya
authors.initials: N
authors.lastname: Kassir
authors.forename: J F
authors.initials: JF
authors.lastname: Marier
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.forename: Doug
authors.initials: D
authors.lastname: Grosenbach
authors.forename: Annie E
authors.initials: AE
authors.lastname: Frimm
authors.forename: Kady M
authors.initials: KM
authors.lastname: Honeychurch
authors.forename: Jarasvech
authors.initials: J
authors.lastname: Chinsangaram
authors.forename: Shanthakumar R
authors.initials: SR
authors.lastname: Tyavanagimatt
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D054833:Isoindoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008252:Macaca fascicularis / Q000821:virology*; D008297:Male; D015233:Models, Statistical; D045908:Mpox, Monkeypox / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D008993:Monkeypox virus / Q000187:drug effects* / Q000254:growth & development; D012899:Smallpox / Q000188:drug therapy* / Q000821:virology; D016019:Survival Analysis; D016896:Treatment Outcome; D012901:Variola virus / Q000187:drug effects / Q000254:growth & development; D010797:Phthalimides
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides