Safety and pharmacokinetics of the antiorthopoxvirus compound ST-246 following repeat oral dosing in healthy adult subjects.
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.
Jordan
Robert
R
SIGA Technologies, Inc., Corvallis, OR 97333, USA.
Chinsangaram
Jarasvech
J
Bolken
Tove' C
TC
Tyavanagimatt
Shanthakumar R
SR
Tien
Deborah
D
Jones
Kevin F
KF
Frimm
Annie
A
Corrado
Michael L
ML
Pickens
Margaret
M
Landis
Patrick
P
Clarke
Jean
J
Marbury
Thomas C
TC
Hruby
Dennis E
DE
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
D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides
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