Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection.
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 fo...
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oai:doaj.org-article:f4abcb9907704df6be4a8674f410129f2021-11-18T07:48:53ZPharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection.1932-620310.1371/journal.pone.0061514https://doaj.org/article/f4abcb9907704df6be4a8674f410129f2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23637845/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Plasma 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.Adams AmantanaYali ChenShanthakumar R TyavanagimattKevin F JonesRobert JordanJarasvech ChinsangaramTove C BolkenJanet M LeedsDennis E HrubyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e61514 (2013) |
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Medicine R Science Q Adams Amantana Yali Chen Shanthakumar R Tyavanagimatt Kevin F Jones Robert Jordan Jarasvech Chinsangaram Tove C Bolken Janet M Leeds Dennis E Hruby Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. |
| description |
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. |
| format |
article |
| author |
Adams Amantana Yali Chen Shanthakumar R Tyavanagimatt Kevin F Jones Robert Jordan Jarasvech Chinsangaram Tove C Bolken Janet M Leeds Dennis E Hruby |
| author_facet |
Adams Amantana Yali Chen Shanthakumar R Tyavanagimatt Kevin F Jones Robert Jordan Jarasvech Chinsangaram Tove C Bolken Janet M Leeds Dennis E Hruby |
| author_sort |
Adams Amantana |
| title |
Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. |
| title_short |
Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. |
| title_full |
Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. |
| title_fullStr |
Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. |
| title_full_unstemmed |
Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. |
| title_sort |
pharmacokinetics and interspecies allometric scaling of st-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/f4abcb9907704df6be4a8674f410129f |
| work_keys_str_mv |
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