title: Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor.
abstract: ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection.
authors.affiliation: SIGA Technologies, Inc., 4575 SW Research Way, Corvallis, OR 97330, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Deborah
authors.initials: D
authors.lastname: Tien
authors.forename: Tove' C
authors.initials: TC
authors.lastname: Bolken
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Jones
authors.forename: Shanthakumar R
authors.initials: SR
authors.lastname: Tyavanagimatt
authors.forename: Josef
authors.initials: J
authors.lastname: Strasser
authors.forename: Annie
authors.initials: A
authors.lastname: Frimm
authors.forename: Michael L
authors.initials: ML
authors.lastname: Corrado
authors.forename: Phoebe G
authors.initials: PG
authors.lastname: Strome
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001549:Benzamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005215:Fasting; D006801:Humans; D054833:Isoindoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D009503:Neutropenia / Q000139:chemically induced; D018155:Orthopoxvirus / Q000187:drug effects* / Q000235:genetics; D010797:Phthalimides
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides