Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor.
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 ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246.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.
Jordan
Robert
R
SIGA Technologies, Inc., 4575 SW Research Way, Corvallis, OR 97330, USA.
Tien
Deborah
D
Bolken
Tove' C
TC
Jones
Kevin F
KF
Tyavanagimatt
Shanthakumar R
SR
Strasser
Josef
J
Frimm
Annie
A
Corrado
Michael L
ML
Strome
Phoebe G
PG
Hruby
Dennis E
DE
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
D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides