title: Safety and pharmacokinetics of the antiorthopoxvirus compound ST-246 following repeat oral dosing in healthy adult subjects.
abstract: ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies.
authors.affiliation: SIGA Technologies, Inc., Corvallis, OR 97333, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Jarasvech
authors.initials: J
authors.lastname: Chinsangaram
authors.forename: Tove' C
authors.initials: TC
authors.lastname: Bolken
authors.forename: Shanthakumar R
authors.initials: SR
authors.lastname: Tyavanagimatt
authors.forename: Deborah
authors.initials: D
authors.lastname: Tien
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Jones
authors.forename: Annie
authors.initials: A
authors.lastname: Frimm
authors.forename: Michael L
authors.initials: ML
authors.lastname: Corrado
authors.forename: Margaret
authors.initials: M
authors.lastname: Pickens
authors.forename: Patrick
authors.initials: P
authors.lastname: Landis
authors.forename: Jean
authors.initials: J
authors.lastname: Clarke
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Marbury
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D018155:Orthopoxvirus / Q000187:drug effects*; D011213:Poxviridae Infections / Q000188:drug therapy; D055815:Young Adult; D010797:Phthalimides
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides
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