TABLE 1

Physicochemical and PK parameters of atomoxetine used in the PBPK model development

Parameter	Value	Reference
Physicochemical
Molecular Weight (g/mol)	255.36	Stattera NDA
Log P	3.9	NDA
pK_a	9.8	NDA
f_u	0.025	NDA
B/P	0.623	Simcyp prediction toolbox
Absorption
F_a	0.96
k_a (l/h)	1.2	Optimized
Q_gut (l/h)	11.9	Simcyp prediction toolbox
Distribution
V_ss (l/kg)	0.74	Simcyp prediction  full PBPK method 2
Metabolism/elimination
CL_i.v. (l/h)	16.3	NDA
CL_r (l/h)	0.185	Sauer et al. (2003)
f_m,CYP2D6	0.876
Recombinant CL_int (μl/min/pmol)
CYP2D6	25.4
CYP2C19	1.84
P450 enzyme abundance (pmol/mg microsomal protein)
CYP2D6 EM	8 (61)^{^a}	Simcyp default value
CYP2C19 EM	14 (40)^{^a}	Optimized
Interaction
CYP2D6 K_i (μM)	34.3	Sauer et al. (2004)
CYP3A4 K_i (μM)	3.6	Sauer et al. (2004)

B/P, blood-to-plasma ratio; CL_i.v., clearance after intravenous administration; CL_r, renal clearance; F_a, fraction absorbed; f_m, fraction metabolized; f_u, fraction unbound in plasma; k_a, absorption rate constant; K_i, inhibition constant; Log P, log octanol:water partition coefficient; Q_gut, drug absorption flow to intestine; V_ss, volume of distribution at steady state.
↵^a Mean value (coefficient of variance).