TABLE 1

Physicochemical and in vitro ADME parameters used in Simcyp for clopidogrel, 2-oxo-clopidogrel, and active metabolite (clopi-H4)

Parameters			Value Implemented in Simcyp	Source Data
Clopidogrel
Physicochemical	MW (g/mol)		321.8	Internal data
	Log P_o:w		3.89
	Compound type		Monoprotic acid
	Pka		4.55
	Hematocrit (%)		45.0	Simcyp library
Absorption	Absorption model/input type		First order	—
	fa; Ka (h⁻¹)		0.5; 0.5	Internal data
	P_eff_{, man} (10⁻⁴ cm/s)		0.466	Predicted		P_caco2 = 0.399×10⁻⁶ cm/s
	Formulation		Solution	—
	fu_Gut		0.02	Set equal to fu_p
Distribution	Distribution model		Full PBPK model	—
	Vss (l/kg)		Predicted, 0.217	Prediction method		Rodgers et al. (2005a, b); Rodgers and Rowland (2006, 2007)
	B/P ratio		Predicted; 0.72	Prediction method		Uchimura et al. (2010)
	fu_p		0.02	Internal data
Metabolism	Clearance type		Enzyme kinetics
	In vitro metabolic system		Human recombinant P450 isoforms	Kazui et al. (2010)
	rhCYP1A2	V_max (pmol/min per pmol)	2.27
		K_M (μM)	1.58
		fu_mic	0.015
	rhCYP2B6	V_max (pmol/min per pmol)	7.66
		K_M (μM)	2.08
		fu_mic	0.015
	rhCYP2C19	V_max (pmol/min per pmol)	7.52
		K_M (μM)	1.12
		fu_mic	0.015	N.B.: fu_mic obtained using the prediction toolbox and refined by sensitivity analysis
	Additional systemic clearance (l/h)		600	Representing about 90% of clopidogrel clearance (esterase-dependent pathway)
2-Oxo-clopidogrel (primary metabolite)
Physicochemical	MW (g/mol)		337.8	Internal data
	Log P_o:w		2.96
	Compound type		Monoprotic acid
	Pka		3.41
	Hematocrit (%)		45.0	Simcyp library
Distribution	Distribution model		Minimal PBPK model	—
	Vss (l/kg)		0.100	Sensitivity analysis
	B/P ratio		Predicted; 1.00	Prediction method		Uchimura et al. (2010)
	fu_p		Predicted; 0.0310	Prediction method		Lobell and Sivarajah (2003)
Metabolism	Clearance type		Enzyme kinetics
	In vitro metabolic system		Human recombinant P450 isoforms	Kazui et al. (2010)
	rhCYP2B6	V_max (pmol/min per pmol)	2.48
		K_M (μM)	1.62
		fu_mic	0.180
	rhCYP2C9	V_max (pmol/min per pmol)	0.855
		K_M (μM)	18.1
		fu_mic	0.180
	rhCYP2C19	V_max (pmol/min per pmol)	9.06
		K_M (μM)	12.1
		fu_mic	0.180
	rhCYP3A4	V_max (pmol/min per pmol)	3.63
		K_M (μM)	27.8
		fu_mic	0.180	N.B.: fu_mic obtained using the prediction toolbox and refined by sensitivity analysis
	Additional clearance	HLM Cl_int (μl/min per mg)	50	Representing about 50% of the total clearance (esterase-dependent pathway)
	Additional clearance	fu_mic	0.180
	Active uptake into hepatocyte		2	Sensitivity analysis
Clopi-H4 (secondary metabolite = active metabolite)
Physicochemical	MW (g/mol)		355.8	Internal data
	Log P_o:w		3.60
	Compound type		Diprotic acid
	Pka 1; Pka 2		3.20; 5.10
	Hematocrit (%)		45.0	Simcyp library
Distribution	Distribution model		Minimal PBPK model	—
	Vss (l/kg)		Predicted; 0.230	Prediction method	Rodgers et al. (2005a, b); Rodgers and Rowland (2006, 2007)
	B/P ratio		Predicted; 0.820	Prediction method	Uchimura et al. (2010)
	fu_p		0.018	Prediction method	Lobell and Sivarajah (2003)
Clearance	Clearance type		In vivo clearance	Representing the direct irreversible covalent binding to platelets
Clearance	CL_po (l/h)		500

B/P, blood-to-plasma ratio; Cl_int, intrinsic clearance; CL_po, oral clearance; fa, fraction absorbed; fu_mic, unbound fraction in microsomes; fu_p, unbound fraction in plasma; K_M, Michaelis-Menten coefficient; P_eff, effective permeability; P_o:w, octanol/water partition coefficient; Vss, steady state.