Comparison of the safety and pharmacokinetics of ST-246® after i.v. infusion or oral administration in mice, rabbits and monkeys

ST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (i.v.) formulation may be required for some hospitalized patients who are unable to take oral medication. An i.v. formulation has been evaluated in three spec...

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Bibliographic Details
Published in:	PloS one Vol. 6; no. 8; p. e23237
Main Authors:	Chen, Yali, Amantana, Adams, Tyavanagimatt, Shanthakumar R, Zima, Daniela, Yan, X Steven, Kasi, Gopi, Weeks, Morgan, Stone, Melialani A, Weimers, William C, Samuel, Peter, Tan, Ying, Jones, Kevin F, Lee, Daniel R, Kickner, Shirley S, Saville, Bradley M, Lauzon, Martin, McIntyre, Alan, Honeychurch, Kady M, Jordan, Robert, Hruby, Dennis E, Leeds, Janet M
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 15-08-2011 Public Library of Science (PLoS)
Subjects:	Administration, Oral Animals Antiviral agents Antiviral Agents - administration & dosage Antiviral Agents - adverse effects Antiviral Agents - pharmacokinetics Area Under Curve Benzamides - administration & dosage Benzamides - adverse effects Benzamides - pharmacokinetics Bioavailability Biological Availability Central nervous system Comparative analysis Disease control Dose-Response Relationship, Drug Drug dosages Drug Evaluation, Preclinical - methods Eczema Exposure FDA approval Female Half-life Health aspects Humans Immunization Infection Infections Infusions, Intravenous Intravenous administration Isoindoles - administration & dosage Isoindoles - adverse effects Isoindoles - pharmacokinetics Laboratories Macaca fascicularis Male Medicine Metabolic Clearance Rate Mice Mice, Inbred BALB C Monkeys Monkeys & apes Oral administration Pharmacokinetics Pharmacology Plasma physics Primates Rabbits Safety regulations Smallpox Species Studies Time Factors Tissue Distribution Toxicity Toxicology Tremor - chemically induced Vaccines Viruses Oregon United States > US Nevada
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Summary:	ST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (i.v.) formulation may be required for some hospitalized patients who are unable to take oral medication. An i.v. formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation. The pharmacokinetics of ST-246 after i.v. infusions in mice, rabbits and nonhuman primates (NHP) were compared to those obtained after oral administration. Ten minute i.v. infusions of ST-246 at doses of 3, 10, 30, and 75 mg/kg in mice produced peak plasma concentrations ranging from 16.9 to 238 µg/mL. Elimination appeared predominately first-order and exposure dose-proportional up to 30 mg/kg. Short i.v. infusions (5 to 15 minutes) in rabbits resulted in rapid distribution followed by slower elimination. Intravenous infusions in NHP were conducted at doses of 1 to 30 mg/kg. The length of single infusions in NHP ranged from 4 to 6 hours. The pharmacokinetics and tolerability for the two highest doses were evaluated when administered as two equivalent 4 hour infusions initiated 12 hours apart. Terminal elimination half-lives in all species for oral and i.v. infusions were similar. Dose-limiting central nervous system effects were identified in all three species and appeared related to high C(max) plasma concentrations. These effects were eliminated using slower i.v. infusions. Pharmacokinetic profiles after i.v. infusion compared to those observed after oral administration demonstrated the necessity of longer i.v. infusions to (1) mimic the plasma exposure observed after oral administration and (2) avoid C(max) associated toxicity. Shorter infusions at higher doses in NHP resulted in decreased clearance, suggesting saturated distribution or elimination. Elimination half-lives in all species were similar between oral and i.v. administration. The administration of ST-246 was well tolerated as a slow i.v. infusion.
Bibliography:	Conceived and designed the experiments: JML YC KMH RJ AA SRT DEH KFJ BMS. Performed the experiments: DZ XSY GK SSK DL KFJ MW WCW MAS AM ML BMS. Analyzed the data: JML YC AA KFJ SRT. Contributed reagents/materials/analysis tools: GK MW WCW MAS PS YT. Wrote the paper: JML YC KMH RJ AA KFJ.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0023237