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.

Preclinical Pharmacokinetics and Safety of Intravenous RTD-1

“…Single-dose PK data from mice, rats, cynomolgus monkeys, and a vervet was used to predict human PK parameters using simple allometry. The relationship between CL or V ss was obtained from the NCA, and the body weight was described using the following equation Y = a × BW b , where Y is the PK parameter (e.g., CL or V ss ), BW is the body weight of the species, is an allometric coefficient, and b is an allometric exponent ( 33 , 37 ). Linear regression was performed on log-transformed data.…”

Therapeutic strategies for human poxvirus infections: Monkeypox (mpox), smallpox, molluscipox, and orf

“…Tecovirimat has also proven effective in the postexposure prophylaxis and therapy of rabbitpox in rabbit models [ 49 ]. From a pharmacokinetic viewpoint, the dog showed the lowest, and the monkey the highest half-life time in an interspecies allometric scaling of tecovirimat [ 50 ]. Still, in 2013 it became also known that tecovirimat was effective against vaccinia virus infection in immunodeficient mice with partial T-cell reconstitution [ 51 ].…”

All That We Need to Know About the Current and Past Outbreaks of Monkeypox: A Narrative Review

“…Tecovirimat (sold under brand name TPOXX) is a promising antiviral agent that exhibits potent anti-poxvirus activity and a low level of cytotoxicity. The animal models that best fulfilled all the criteria laid down under the Animal Rule to establish the antiviral efficacy of a molecule were the IV challenge of cynomolgus macaques with MPVX, the rabbitpox virus intradermal challenge model in rabbits, and the intranasal challenge model of ectromelia virus (mousepox) in Balb/C mice [23][24][25][26][27]. Subsequent trials in healthy human volunteers to ascertain toxicity, pharmacokinetics (PK) and pharmacodynamics (PD) parameters, human dose equivalents, and a pivotal clinical trial in 449 adults led to the approval of TPOXX on July 13, 2018, for SPX [28][29][30][31][32].…”