TABLE 1

simCYP user inputs for GlaxoSmithKline (GSK) compounds used in the case studies

DrugPhysical/Chemical PropertiesAbsorption ParametersDistribution ParametersElimination ParametersInteraction Parameters
GSK1cLogP: 1.8Model: 1st orderModel: Full PBPKCL type: enzyme kinetics (HLM)
Type: MBMDCK permeability: 200 nm/sVss: predictedCLint: CYP3A4: 14.5 µl/min/mg
pKa: 8.64fumic: 0.958
B:P 0.75Additional CYP: 2.5 µl/min/mg
fup: 0.193CLR 0.75 l/h
GSK5cLogP: 5.03Model: 1st order1 compartmentEnzyme kinetics (HLM)
Type: MBInput fa: 1Vss: user input: 5 L/kgCLint:
pKa: 8.69Input ka: 1CYP3A4:
B:P: 165.06 µl/min/mg
fup: 0.006fumic: 0.164
GSK6cLogP: 3.9Model: 1st orderModel: Minimal PBPKEnzyme kinetics (HLM)
Type: NMDCK permeability: 143 nm/sVss: predictedCLint:
B:P 1CYP3A4: 42.3
fup: 0.029CYP2D6: 0.5 µL/min/mg
fumic (predicted): 0.33
GSK19cLogP: 5.7Model: 1st orderModel: Minimal PBPKEnzyme kinetics (rCYPs)KI (μM) CYP3A4 0.143
Type: MBMDCK permeability: 72 nm/sVss: predictedCLint: CYP2C9: 0.433Kinact (hr−1) CYP3A4 2.77
pKa: 7.26Input fa: 0.85CYP2C19: 3.556
B:P: 0.61Input ka: 1CYP3A4: 2.801
fup: 0.02µl/min/pmol CYPCLR: 0.085 l/h
GSK38cLogP: 3.6Model: 1st orderModel: Minimal PBPKEnzyme kinetics (HLM)3A4 EC50 (μM): 0.26
Type: MAMDCK permeability: 279 nm/sVss: predictedCLint: CYP3A4: 14.1 µl/min/mg3A4 Emax: 5.47
pKa: 12.07Input fa: 0.66Additional hepatic CLint: 5.0 µl/min/mg
B:P: 0.6Input ka: 0.3Additional CLsys: 1.0 l/h
fup: 0.003fumic (predicted): 0.935
  • CL, clearance; CLint, hepatic intrinsic clearance; CLsys, systemic clearance; fumic, fraction unbound in microsomes; fup, fraction unbound in plasma; HLM, human liver microsomes; Kinact, maximum inactivation rate constant; MDCK, Madin-Darby canine kidney cell line; PBPK, physiologically based pharmacokinetics; Vss, volume of distribution at steady state. CLR, renal clearance; B:P, blood to plasma ratio; Emax, maximal induction; KI, inactivation constant; N, neutral; MA, monoprotic acid; MB, monoprotic base; fa, fraction absorbed; ka, absorption rate constant