Pharmacokinetics and Interspecies Allometric Scaling of ST-246, an Oral Antiviral Therapeutic for Treatment of Orthopoxvirus InfectionReport as inadecuate




Pharmacokinetics and Interspecies Allometric Scaling of ST-246, an Oral Antiviral Therapeutic for Treatment of Orthopoxvirus Infection - Download this document for free, or read online. Document in PDF available to download.

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.



Author: Adams Amantana , Yali Chen, Shanthakumar R. Tyavanagimatt, Kevin F. Jones, Robert Jordan, Jarasvech Chinsangaram, Toveā€² C. Bolk

Source: http://plos.srce.hr/



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