Pharmacokinetic and pharmacodynamic modeling to determine the dose of ST-246 to protect against smallpox in humans

Abstract

Although smallpox has been eradicated, the United States government considers it a "material threat" and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the population.

Fig 1

Comparison of predicted AUC, C_max, and C_min for orthopoxvirus-infected humans and NHPs based on the population PK model of infected monkeys. (A and B) Steady-state values predicted for AUC, C_max, and C_min in infected humans after an ST-246 dose of 400 mg (A) or 600 mg (B). The solid line is the median predicted value for infected humans for each plot, while the dashed lines represent the 5th and 95th percentile values simulated for an infected human population. The box plots (bottom and top brackets are minimum and maximum values for each box plot, light line is median, and dark portion is the 25th to 75th percentage for simulated population) showing values that were simulated for NHP values at discrete doses from 3 mg/kg to 18 mg/kg ST-246 are overlaid on the corresponding human parameter values. The y-axis parameter and units are shown at the top of each individual plot.

Fig 2

Kaplan-Meier survival curve for efficacy studies in NHPs using 14 days of ST-246 treatment. Shown is combined survival analysis of NHPs treated QD for 14 days at doses ranging from 0.3 to 20 mg/kg ST-246 starting either 3, 4, or 5 (10-mg/kg dose group only) days postinfection with a lethal dose of MPXV. The median time to death for placebo-treated animals (n = 23) was 14 days after infection. Doses above 20 mg/kg had 100% survival and are not shown.

Fig 3

Receiver operator characteristic analysis of NHP ST-246 treatment using exposure levels as the cutoff parameter. ROC analysis of NHP treatments versus survival outcome versus the exposure determined that exposure equal to or greater than 0.50 mg · h/(liters/kg) was the cutoff value for survival for the 67 NHPs with sensitivity and specificity values of 92.86% and 97.44%, respectively. The ROC tree shows the number of NHPs in the analysis, along with the number of NHPs that died in the two groups.

Fig 4

(A) Plasma concentration-time curves for uninfected humans and NHPs over a range of doses relevant to efficacious-dose selection. Shown is a semilogarithmic graph of steady-state plasma concentration-time curves for 400-mg and 600-mg doses in healthy humans compared to 3-mg/kg and 10-mg/kg doses in uninfected NHPs. The means and standard deviations of the means are plotted for all curves. The NHP lines are dashed, while the lines for the human values are dotted (400 mg) and solid (600 mg). (B) Comparison of individual exposure levels in uninfected humans at two doses compared to the lowest efficacious dose in NHPs. Individual (×) and mean (solid squares) AUC_inf values at steady state for 400- and 600-mg doses of ST-246 are shown. The black dashed line shows the AUC_inf value at steady state for the 3-mg/kg dose in uninfected NHPs.