ST-246 antiviral efficacy in a nonhuman primate monkeypox model: determination of the minimal effective dose and human dose justification.
Therapeutics for the treatment of pathogenic orthopoxvirus infections are being sought. In the absence of patients with disease, animal models of orthopoxvirus disease are essential for evaluation of the efficacies of antiviral drugs and establishment of the appropriate dose and duration of human therapy. Infection of nonhuman primates (NHP) by the intravenous injection of monkeypox virus has been used to evaluate a promising therapeutic drug candidate, ST-246. ST-246 administered at 3 days postinfection (which corresponds to the secondary viremia stage of disease) at four different doses (from 100 mg/kg of body weight down to 3 mg/kg) once a day for 14 days was able to offer NHP 100% protection from a lethal infection with monkeypox virus and reduce the viral load and lesion formation. In NHP, the administration of ST-246 at a dose of 10 mg/kg/day for 14 days resulted in levels of blood exposure comparable to the levels attained in humans administered 400 mg in the fed state. These results suggest that administration of an oral dosage of 400 mg once daily for 14 days will be effective for the prevention or treatment of smallpox or monkeypox infections in humans.
Jordan
Robert
R
SIGA Technologies, Inc., 4575 SW Research Way, Suite 230, Corvallis, OR 97333, USA.
Goff
Arthur
A
Frimm
Annie
A
Corrado
Michael L
ML
Hensley
Lisa E
LE
Byrd
Chelsea M
CM
Mucker
Eric
E
Shamblin
Josh
J
Bolken
Tove' C
TC
Wlazlowski
Carly
C
Johnson
Wendy
W
Chapman
Jennifer
J
Twenhafel
Nancy
N
Tyavanagimatt
Shanthakumar
S
Amantana
Adams
A
Chinsangaram
Jarasvech
J
Hruby
Dennis E
DE
Huggins
John
J
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008252:Macaca fascicularis; D045908:Mpox, Monkeypox / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D008993:Monkeypox virus / Q000187:drug effects*; D016896:Treatment Outcome; D010797:Phthalimides
D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides