title: 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: SIGA Technologies Inc., Corvallis, Oregon, USA. aamantana@siga.com
authors: Adams
authors: A
authors: Amantana
authors: Yali
authors: Y
authors: Chen
authors: Shanthakumar R
authors: SR
authors: Tyavanagimatt
authors: Kevin F
authors: KF
authors: Jones
authors: Robert
authors: R
authors: Jordan
authors: Jarasvech
authors: J
authors: Chinsangaram
authors: Tove C
authors: TC
authors: Bolken
authors: Janet M
authors: JM
authors: Leeds
authors: Dennis E
authors: DE
authors: Hruby
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001835:Body Weight; D004285:Dogs; D005260:Female; D006207:Half-Life; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018155:Orthopoxvirus; D011213:Poxviridae Infections / Q000188:drug therapy*; D011817:Rabbits; D010797:Phthalimides
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides
references: J Clin Pharmacol. 2003 Jul;43(7):692-7
references: 12861964
references: Xenobiotica. 1996 Sep;26(9):887-95
references: 8893036
references: J Pharmacokinet Biopharm. 1986 Apr;14(2):131-55
references: 3746636
references: Comp Biochem Physiol C Comp Pharmacol Toxicol. 1992 Oct;103(2):249-53
references: 1360380
references: Clin Pharmacokinet. 1999 Mar;36(3):211-31
references: 10223169
references: J Appl Toxicol. 1989 Oct;9(5):331-8
references: 2592732
references: J Pharmacokinet Biopharm. 1982 Dec;10(6):649-61
references: 7182460
references: Am J Trop Med Hyg. 2007 Apr;76(4):768-73
references: 17426185
references: AAPS PharmSci. 2001;3(4):E29
references: 12049492
references: Cancer Chemother Rep. 1975 Jul-Aug;59(4):777-93
references: 1175169
references: Int J Clin Pharmacol Ther. 1997 Dec;35(12):541-52
references: 9455711
references: Antimicrob Agents Chemother. 2009 Jun;53(6):2620-5
references: 19349521
references: Antimicrob Agents Chemother. 2009 May;53(5):1817-22
references: 19223621
references: Antimicrob Agents Chemother. 2007 Feb;51(2):689-95
references: 17116683
references: J Pharm Sci. 1996 Apr;85(4):411-4
references: 8901079
references: J Pharmacol Exp Ther. 1997 Oct;283(1):46-58
references: 9336307
references: Regul Toxicol Pharmacol. 1994 Apr;19(2):228-35
references: 8041920
references: Pharm Res. 1993 Jul;10(7):1093-5
references: 8378254
references: Xenobiotica. 1990 Nov;20(11):1201-31
references: 2275215
references: J Pharmacokinet Biopharm. 1982 Jun;10(3):297-316
references: 7175701
references: J Pharmacokinet Biopharm. 1982 Apr;10(2):201-27
references: 7120049
references: Virol J. 2009 Apr 28;6:44
references: 19400954
references: Antiviral Res. 2008 Aug;79(2):121-7
references: 18479761
references: J Pharmacokinet Biopharm. 1980 Apr;8(2):165-76
references: 6107379
references: Antivir Ther. 2007;12(8):1205-16
references: 18240860
references: J Virol. 2005 Oct;79(20):13139-49
references: 16189015
references: Clin Pharmacokinet. 1999 Jan;36(1):1-11
references: 9989339
references: J Clin Pharmacol. 1995 Oct;35(10):957-66
references: 8568013
references: Life Sci. 1996;59(7):579-85
references: 8761347