TABLE 2

Physicochemical and in vitro ADME parameters used in Simcyp for dronedarone

Parameters			Value Implemented in Simcyp	Source Data
Physicochemical	MW (g/mol)		557	Analytical dossier
	Log P_o:w		7.80
	Compound type		Monoprotic base
	Pka		9.30
	Hematocrit (%)		45.0	Simcyp library
Absorption	Absorption model/input type		ADAM model	—
	fa; Ka (h⁻¹)		Predicted; 0.898; 0.816	Predicted using ADAM model
	P_eff, (10⁻⁴ cm/s)		1.98	Predicted	P_caco2 = 5.30 × 10⁻⁶ cm/s
	Formulation		Solid; Controlled-Released	—
	Dissolution-time profile	Time (h): 0, 0.083, 0.167, 0.25, 0.33, 0.42, 0.5, 0.75, 1 and 1.5	Dissolution (%): 0, 6.6, 12.8, 28.5, 38.9, 47.7, 55.2, 75.9, 92.2 and 100	Analytical dossier
	Solubility– pH profile	pH: 3, 4, 5, 6 and 7	Solubility (mg/ml): 1.6, 1.6, 1.5, 0.1 and 0.05	Analytical dossier
	fu_Gut		1.00	—
Distribution	Distribution model		Minimal PBPK model	—
	Vss (l/kg)		10	Analytical dossier; Pop_Pk analysis
	B:P ratio		1.00	Analytical dossier
	fu_p		0.003	Analytical dossier
Metabolism	Clearance type		Enzyme kinetics
	In vitro metabolic system		Recombinant	Analytical dossier
	rhCYP3A4	V_max  (pmol/min per pmol)	13.7
		K_M (μM)	4.2
		fu_mic	0.0011
	rhCYP3A5	V_max  (pmol/min per pmol)	4.87
		K_M (μM)	3.10
		fu_mic	0.0011
	Additional liver clearance	Cl_int  (l/min per mg)	40
	Additional liver clearance	fu_mic	0.0011	N.B.: fu_mic obtained using the prediction toolbox and refined by sensitivity analysis
Interaction	CYP2B6 (comp. inhibition)	K_i (μM)	12.0	Analytical dossier
	CYP2B6 (comp. inhibition)	fu_mic	0.0011
	CYP2D6 (comp. inhibition)	K_i (μM)	5.0
	CYP2D6 (comp. inhibition)	fu_mic	0.0011
	CYP3A4 (MBI)	K_i (μM)	2.44
		K_inact (h⁻¹)	9.16
		fu_mic	0.0011

fa, fraction absorbed; fu_p, unbound fraction in plasma; fu_mic, unbound fraction in microsomes; Ka, first-order rate constant; K_i and K_inact, mechanism-based inactivation parameters; P_eff, effective permeability in human; Vss, steady state.