PBPK model input parameters

ParameterDescriptionUnitParameter Value
Physicochemical dataa 309.4358.4464.6371.5268.7280.4326.8312.4314.4
 MWMolecule weightg/mol
 log P/log DOctanol: buffer partition coefficient4.24/2.342.12/0.724.3/3.366.8/4.622.17/1.655.03/2.513.5/2.963.5/2.150.67/−0.78
 pKa/typeDissociation constant9.3/base8.8/base8.3/base8.8/base6/base9.4/base7.75/base7.2/base8.2/2.7 diprotic base
 BPBlood-to-plasma partition ratio0.760.720.940.890.840.930.8250.730.90
 FuFraction unbound in plasma0.1460.2620.08730.000350.6380.2610.09250.3270.912
 KaAbsorption rate constant1/h1.214, lag time of 0.4 hours0.391.1212.2.21.360.38
 Fu,gutUnbound fraction of drug in gut enterocytes. Either default of 1 or predicted value used10.1921111111
 Pcaco-2Caco-2 permeability× 10−6 cm/sMech-eff modelMech-eff model64.4Mech-eff modelPSA/HBDPSA/HBDPSA/HBD
 Peff,manHuman jejunum permeability× 10−4 cm/s8.7154.096.958.567.877.830.94
 VssDistribution volume at steady-state after IV or predicted using Method 2l/kg0.9666.35.615.73.5917.
 VssDistribution modell/kgMinimal PBPK modelFull PBPKFull PBPKFull PBPKFull PBPKMinimal PBPKMinimal PBPKMinimal PBPKFull PBPK
 CLint-HLMHuman liver microsomal protein in vitro intrinsic clearanceµl/min/mg protein181861431418<3<3
 CLint- HepatocytesHepatocytes in vitro intrinsic clearanceµl/min per 106 cells91129439520.6
 Fm (% FMO) Fraction metabolized contribution%539638283821232326
 CLint - rFMOFMO in-vitro intrinsic clearance and remaining metabolic CL was accounted via major metabolizing enzyme via HLM in enzyme kinetics or via rCYP if P450 contribution knownµl/min/pmol protein or µl/min/mg protein for HLMFMO1 = 0.44,FMO3 = 0.29,FMO5 = 0.001,CYP2D6 = 8.5FMO1 = 0.79,FMO3 = 0.118,FMO5 = 0.0.052,CYP3A4 = 0.87FMO1 = 0.24,FMO3 = 0.48,FMO5 = 0,CYP3A4 = 39FMO1 = 0.083,FMO3 = 0,FMO5 = 0,CYP3A4 = 3.6FMO1 = 0.018,FMO3 = 0.031,FMO5 = 0.003,CYP3A4 = 2.9FMO1 = 0.163,FMO3 = 0.013, FMO5 = 0.001,CYP1A2 = 0.058,2C19 = 2.36,2D6 = 47,3A4 = 0.021,Additional HLM CL = 1.52FMO1 = 0.031,FMO3 = 0,FMO5 = 0,CYP3A4 = 11.1FMO1 = 0.04,FMO3 = 0.006,FMO5 = 0,CYP3A4 = 2.31FMO1 = 0.011,FMO3 = 0.003,FMO5 = 0.028,CYP3A4 = 2.22
 Systemic  clearanceSystemic absolute CL or oral CLl/h9.66b88c87b8c63.7b54c32c26c7.56b
 Renal  clearanceRenal CLl/h0.241.524.6
 Fu,micUnfound fraction in microsomes0.351.
 Fu,incUnfound fraction in hepatocytes0.740.880.210.0030.870.650.330.860.98
  • HBD, hydrogen bond donor; PSA, polar surface area; rCYP, recombinant cytochrome P450; Vss, volume of distribution at steady state. —, data not available or not reported.

  • a Source: AstraZeneca experimental data (Jones et al., 2017).

  • b From intravenous study using references shown in Table 3 for a respective drug.

  • c From oral study using references shown in Table 3 for a respective drug.