Table 4. Observed versus scaled human plasma pharmacokinetics, recommended and given FIH dose levels for ST-246.

Parameter		Scaled	400 (mg)h	600 (mg)i	800 (mg)j
Cl/F (L/h)		254.0a	37.5±14	48.0±25	36.5±7
Cl/F (L/h)		51.4b
VD/F (L)		2311.5c	1248.2±588	1355.6±790	1081.0±459
t1/2 (h)		6.3d	25.8±11	24.3±15	20.7±8
t1/2 (h)		31.2e
Extraction Ratio		0.756f	0.111	0.143	0.109
Extraction Ratio		0.153g
Recommended ST-246 Dose (mg) Determined from Scaled Human Plasma Clearance				ST-246 Dose Levels (mg) administered in Healthy Adult Human Volunteers
485¶				400, 600 & 800

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[26] of the pharmacologically guided approach provided in the United State Food and Drug Administration (USDFA) draft guidance [27] and expressed as follows: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 = 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.

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.

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.