TABLE 1

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

ParametersValue Implemented in SimcypSource Data
Clopidogrel
PhysicochemicalMW (g/mol)321.8Internal data
Log Po:w3.89
Compound typeMonoprotic acid
Pka4.55
Hematocrit (%)45.0Simcyp library
AbsorptionAbsorption model/input typeFirst order
fa; Ka (h−1)0.5; 0.5Internal data
Peff, man (10−4 cm/s)0.466PredictedPcaco2 = 0.399×10−6 cm/s
FormulationSolution
fuGut0.02Set equal to fup
DistributionDistribution modelFull PBPK model
Vss (l/kg)Predicted, 0.217Prediction methodRodgers et al. (2005a, b); Rodgers and Rowland (2006, 2007)
B/P ratioPredicted; 0.72Prediction methodUchimura et al. (2010)
fup0.02Internal data
MetabolismClearance typeEnzyme kinetics
In vitro metabolic systemHuman recombinant P450 isoformsKazui et al. (2010)
rhCYP1A2Vmax (pmol/min per pmol)2.27
KM (μM)1.58
fumic0.015
rhCYP2B6Vmax (pmol/min per pmol)7.66
KM (μM)2.08
fumic0.015
rhCYP2C19Vmax (pmol/min per pmol)7.52
KM (μM)1.12
fumic0.015N.B.: fumic obtained using the prediction toolbox and refined by sensitivity analysis
Additional systemic clearance (l/h)600Representing about 90% of clopidogrel clearance (esterase-dependent pathway)
2-Oxo-clopidogrel (primary metabolite)
PhysicochemicalMW (g/mol)337.8Internal data
Log Po:w2.96
Compound typeMonoprotic acid
Pka3.41
Hematocrit (%)45.0Simcyp library
DistributionDistribution modelMinimal PBPK model
Vss (l/kg)0.100Sensitivity analysis
B/P ratioPredicted; 1.00Prediction methodUchimura et al. (2010)
fupPredicted; 0.0310Prediction methodLobell and Sivarajah (2003)
MetabolismClearance typeEnzyme kinetics
In vitro metabolic systemHuman recombinant P450 isoformsKazui et al. (2010)
rhCYP2B6Vmax (pmol/min per pmol)2.48
KM (μM)1.62
fumic0.180
rhCYP2C9Vmax (pmol/min per pmol)0.855
KM (μM)18.1
fumic0.180
rhCYP2C19Vmax (pmol/min per pmol)9.06
KM (μM)12.1
fumic0.180
rhCYP3A4Vmax (pmol/min per pmol)3.63
KM (μM)27.8
fumic0.180N.B.: fumic obtained using the prediction toolbox and refined by sensitivity analysis
Additional clearanceHLM Clint (μl/min per mg)50Representing about 50% of the total clearance (esterase-dependent pathway)
fumic0.180
Active uptake into hepatocyte2Sensitivity analysis
Clopi-H4 (secondary metabolite = active metabolite)
PhysicochemicalMW (g/mol)355.8Internal data
Log Po:w3.60
Compound typeDiprotic acid
Pka 1; Pka 23.20; 5.10
Hematocrit (%)45.0Simcyp library
DistributionDistribution modelMinimal PBPK model
Vss (l/kg)Predicted; 0.230Prediction methodRodgers et al. (2005a, b); Rodgers and Rowland (2006, 2007)
B/P ratioPredicted; 0.820Prediction methodUchimura et al. (2010)
fup0.018Prediction methodLobell and Sivarajah (2003)
ClearanceClearance typeIn vivo clearanceRepresenting the direct irreversible covalent binding to platelets
CLpo (l/h)500
  • B/P, blood-to-plasma ratio; Clint, intrinsic clearance; CLpo, oral clearance; fa, fraction absorbed; fumic, unbound fraction in microsomes; fup, unbound fraction in plasma; KM, Michaelis-Menten coefficient; Peff, effective permeability; Po:w, octanol/water partition coefficient; Vss, steady state.