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.

Figure 1. Molecular structure of ST-246.

Figure 2. Plots of mean plasma concentration versus time profiles in BALB/c mice following repeat oral administrations of ST-246 by gavage at a dose of 2000 mg/kg for 28 consecutive days.

The adjacent plot represents the corresponding semi-logarithmic plot.

Figure 3. Plots of mean plasma concentration versus time profiles in New Zealand white Hra: (NZW) SPF albino rabbits following repeat oral administrations of ST-246 by gavage at a dose of 100 mg/kg seven consecutive days.

The adjacent plot represents the corresponding semi-logarithmic plot.

Figure 4. Plots of mean plasma concentration versus time profiles in cynomolgus monkeys following repeat oral administrations of ST-246 by gavage at a dose of 100 mg/kg for 28 consecutive days.

The adjacent plot represents the corresponding semi-logarithmic plot.

Figure 5. Plots of mean plasma concentration versus time profiles in beagle dogs, following repeat oral administrations of ST-246 by gavage at a dose of 30 mg/kg seven consecutive days.

The adjacent plot represents the corresponding semi-logarithmic plot.

Figure 6. Linear regression analysis of log-transformed plasma clearance for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, cynomolgus monkeys and beagle dogs versus log-transformed corresponding animal body weight, following oral administration of ST-246 by gavage at a dose of 2000, 100, 100 and 30 mg/kg, respectively.

Figure 7. Linear regression analysis of log-transformed plasma clearance multiplied by corresponding maximum life span potential (MLP) for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, cynomolgus monkeys and beagle dogs versus log-transformed corresponding animal body weight, following oral administration of ST-246 by gavage at a dose of 2000, 100, 100 and 30 mg/kg, respectively.

Figure 8. Linear regression analysis of log- transformed apparent volume of distribution for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, cynomolgus monkeys and beagle dogs versus log-transformed corresponding animal body weight, following oral (gavage) administration of ST-246 by gavage at a dose of 2000, 100, 100 and 30 mg/kg, respectively.