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Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection.

Abstract
Plasma pharmacokinetics of ST-246, smallpox therapeutic, was evaluated in mice, rabbits, monkeys and dogs following repeat oral administrations by gavage. The dog showed the lowest Tmax of 0.83 h and the monkey, the highest value of 3.25 h. A 2- to 4-fold greater dose-normalized Cmax was observed for the dog compared to the other species. The mouse showed the highest dose-normalized AUC, which was 2-fold greater than that for the rabbit and monkey both of which by approximation, recorded the lowest value. The Cl/F increased across species from 0.05 L/h for mouse to 42.52 L/h for dog. The mouse showed the lowest VD/F of 0.41 L and the monkey, the highest VD/F of 392.95 L. The calculated extraction ratios were 0.104, 0.363, 0.231 and 0.591 for mouse, rabbit, monkey and dog, respectively. The dog showed the lowest terminal half-life of 3.10 h and the monkey, the highest value of 9.94 h. The simple allometric human VD/F and MLP-corrected Cl/F were 2311.51 L and 51.35 L/h, respectively, with calculated human extraction ratio of 0.153 and terminal half-life of 31.20 h. Overall, a species-specific difference was observed for Cl/F with this parameter increasing across species from mouse to dog. The human MLP-corrected Cl/F, terminal half-life, extraction ratios were in close proximity to the observed estimates. In addition, the first-in-humans (FIH) dose of 485 mg, determined from the MLP-corrected allometry Cl/F, was well within the dose range of 400 mg and 600 mg administered in healthy adult human volunteers.
AuthorsAdams Amantana, Yali Chen, Shanthakumar R Tyavanagimatt, Kevin F Jones, Robert Jordan, Jarasvech Chinsangaram, Tove C Bolken, Janet M Leeds, Dennis E Hruby
JournalPloS one (PLoS One) Vol. 8 Issue 4 Pg. e61514 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23637845 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antiviral Agents
  • Benzamides
  • Isoindoles
  • ST-246
Topics
  • Administration, Oral
  • Adult
  • Animals
  • Antiviral Agents (administration & dosage, pharmacokinetics)
  • Area Under Curve
  • Benzamides (administration & dosage, blood, pharmacokinetics)
  • Body Weight
  • Dogs
  • Female
  • Half-Life
  • Humans
  • Isoindoles (administration & dosage, blood, pharmacokinetics)
  • Macaca fascicularis
  • Male
  • Mice
  • Orthopoxvirus
  • Poxviridae Infections (drug therapy)
  • Rabbits

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