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.

• Authors: Adams Amantana, Yali Chen, Shanthakumar R Tyavanagimatt, Kevin F Jones, Robert Jordan, Jarasvech Chinsangaram, Tove C Bolken, Janet M Leeds, Dennis E Hruby
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e61514 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23637845 (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
• tecovirimat

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