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.

<p>The adjacent plot represents the corresponding semi-logarithmic plot.</p

Allometric coefficient, allometric exponent and coefficient of determination values from linear regression analysis of pharmacokinetic parameters from BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, cynomolgus monkeys and beagle dogs following repeat oral administration of ST-246 by gavage for 7 consecutive days in New Zealand white Hra: (NZW) SPF albino rabbits and beagle dogs and 28 consecutive days in BALB/c mice and cynomolgus monkeys.

<p>♀ & φ = Values from simple allometry.</p><p>Φ = Values from MLP-corrected allometry.</p

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.

<p>The adjacent plot represents the corresponding semi-logarithmic plot.</p

Plasma pharmacokinetic estimates for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, beagle dogs and cynomolgus monkeys following repeat oral dosing of ST-246 by gavage for 7 consecutive days in New Zealand white Hra: (NZW) SPF albino rabbits and beagle dogs and 28 consecutive days in BALB/c mice and cynomolgus monkeys.

<p>Extraction ratio = Cl/F/Cardiac Output.</p

Observed versus scaled human plasma pharmacokinetics, recommended and given FIH dose levels for ST-246.

<p>Extraction ratio = Cl/F/Cardiac Output.</p><p>¶ = First-in human (FIH) dose calculated by a slight modification (no safety factor applied) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061514#pone.0061514-Mahmood4" target="_blank">[26]</a> of the pharmacologically guided approach provided in the United State Food and Drug Administration (USDFA) draft guidance <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061514#pone.0061514-US1" target="_blank">[27]</a> and expressed as follows:</p><p>Dose (mg) = Animal AUC (h_*µg/mL) × scaled human Cl/F (L/h).</p><p>Where the applied AUC is the lowest observed systemic exposure value among the animal species utilized in this evaluation.</p><p>a = Plasma clearance scaled by simple allometry.</p><p>b = Plasma clearance scaled by MLP-corrected allometry.</p><p>c = Apparent volume of distribution scaled by simple allometry.</p><p>d = t_1/2 calculated from the simple allometry human plasma clearance (Cl/F) and simple allometry human apparent volume of distribution (V_D/F) using the equation: t1_/2 = In2*(V_D/F)_scaled/(Cl/F)_scaled.</p><p>e = t_1/2 calculated from the MLP-corrected allometry human plasma clearance (Cl/F) and simple allometry human apparent volume of distribution (V_D/F) using the equation: t_1/2 = In2*(V_D/F)_scaled/(Cl/F)_scaled.</p><p>f = Extraction ratio calculated from simple allometry human plasma clearance (Cl/F).</p><p>g = Extraction ratio calculated from the MLP-corrected allometry human plasma clearance (Cl/F).</p><p>h = Human pharmacokinetic estimates from a double-blind, randomized, placebo-controlled study following single daily oral administrations of ST-246 (in capsule form) at a dose of 400 mg for 14 days in non-fasted healthy adult human volunteers.</p><p>i = Human pharmacokinetic estimates from a double-blind, randomized, placebo-controlled study following single daily oral administrations of ST-246 (in capsule form) at a dose of 600 mg for 14 days in non-fasted healthy adult human volunteers.</p><p>j = Human pharmacokinetic estimates from a double-blind, randomized, placebo-controlled study following single daily oral administrations of ST-246 (in capsule form) at a dose of 800 mg for 21 days in non-fasted healthy adult human volunteers.</p

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.

<p>The adjacent plot represents the corresponding semi-logarithmic plot.</p