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

Extraction ratio = Cl/F/Cardiac Output.¶ = First-in human (FIH) dose calculated by a slight modification (no safety factor applied) [26] of the pharmacologically guided approach provided in the United State Food and Drug Administration (USDFA) draft guidance [27] and expressed as follows:Dose (mg) = Animal AUC (h*µg/mL) × scaled human Cl/F (L/h).Where the applied AUC is the lowest observed systemic exposure value among the animal species utilized in this evaluation.a = Plasma clearance scaled by simple allometry.b = Plasma clearance scaled by MLP-corrected allometry.c = Apparent volume of distribution scaled by simple allometry.d = t1/2 calculated from the simple allometry human plasma clearance (Cl/F) and simple allometry human apparent volume of distribution (VD/F) using the equation: t1/2 = In2*(VD/F)scaled/(Cl/F)scaled.e = t1/2 calculated from the MLP-corrected allometry human plasma clearance (Cl/F) and simple allometry human apparent volume of distribution (VD/F) using the equation: t1/2 = In2*(VD/F)scaled/(Cl/F)scaled.f = Extraction ratio calculated from simple allometry human plasma clearance (Cl/F).g = Extraction ratio calculated from the MLP-corrected allometry human plasma clearance (Cl/F).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.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.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.