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1 Supplemental Information Article Title:The Proton Pump Inhibitor, Omeprazole, but not Lansoprazole or Pantoprazole, is a Metabolism-Dependent Inhibitor of CYP2C19: Implications for Co-Administration with Clopidogrel p Authors: Brian W. Ogilvie, Phyllis Yerino, Faraz Kazmi, Amin Rostami-Hodjegan, David B. Buckley, Brandy L. Paris, Paul Toren, and Andrew Parkinson. XenoTech, LLC, Lenexa, KS and University of Manchester, & Simcyp Limited, UK. Journal: Drug Metabolism and Disposition
2 Supplemental Table 2 (page 1 of 8) Simcyp Population Based Sim 6/21/ :55 Simcyp : Version SP1 SE(14/0 Substrate Inhibitor 1 Compound Name Sim-S-Mephenytoin Compound Name Omeprazole with MBI Route Oral Route Oral Sub : Dose Units Dose (mg) Inh 1 : Dose Units Dose (mg) Sub : Dose Inh 1 : Dose Start Day Start Day Start Time 9h0m Start Time 9h0m Dosing Regime Single Dose Dosing Regime Multiple Dose Dose Interval (h) PhysChem and Blood Binding Number of Doses Mol Weight (g/mol) PhysChem and Blood Binding log P Compound Type Monoprotic Base Mol Weight (g/mol) pka log P B/P Compound Type Ampholyte Haematocrit pka fu Input User Input pka fu B/P Protein Reference Haematocrit Main Plasma Binding Protein HSA fu Input User Input fu Absorption Protein Reference Main Plasma Binding Protein HSA Absorption Model 1st order Input Type Entered Absorption fa CV fa (%) Absorption Model 1st order ka (1/h) Input Type Entered CV ka (%) fa fu(gut) CV fa (%) Q(Gut) Input Predicted ka (1/h) Q(Gut) (L/h) CV ka (%) Peff,man Type Predicted fu(gut) Permeability Assay Physicochemical Q(Gut) Input Predicted PSA(Ų) Q(Gut) (L/h) HBD Peff,man Type Predicted Permeability Assay MDCK Distribution MDCK(10E-06 cm/s) Reference Compound Multiple Distribution Model Minimal PBPK Model Reference Compound Value (10E-06 cm/s) Vss mode Entered Scalar Vss (L/kg) CV Vss (%) Distribution Elimination Distribution Model Minimal PBPK Model Vss mode Entered Vss (L/kg) Allometric Scaling Not Used CV Vss (%) Clearance Type Enzyme Kinetics Elimination Ontogeny Profile No Profile Used In vitro metabolic system HLM Use Allelic variants for CYP2C9 No Allometric Scaling Not Used Pathway N-demethylation Clearance Type Enzyme Kinetics Enzyme CYP2B6 Ontogeny Profile No Profile Used Vmax In vitro metabolic system Recombinant Km Use Allelic variants for CYP2C9 No fu mic Pathway 5-OH Pathway 4-OH Enzyme CYP2C19
3 Supplemental Table 2 (page 2 of 8) Enzyme CYP2C19 Vmax Vmax Km Km fu mic fu mic Pathway 5-OH Additional Hep Ontogeny Profile No Profile Used Enzyme CYP3A4 Biliary CLint (Hep)(µL/min/10^6) Vmax CV Biliary CLint (Hep)(%) Km Active Uptake into Hepatocyte fu mic CL R (L/h) Additional Systemic Clearance CV (%) Pathway Sulfoxidation Enzyme CYP3A4 Vmax Km fu mic Additional Hep Ontogeny Profile No Profile Used Biliary CLint (Hep)(µL/min/10^6) CV Biliary CLint (Hep)(%) Active Uptake into Hepatocyte CL R (L/h) Additional Systemic Clearance CV (%) CYPs Interaction Enzyme CYP2C19 Ki (µm) fu mic MBI Kapp (µm) MBI Kinact (1/h) MBI fu mic 0.750
4 Supplemental Table 2 (page 3 of 8) mulator 01/2011) Trial Design Software Version Detail Use Pop Representative Yes Source File Location C:\Program Files\Simcyp\Simcyp Simulator v10 Population Size n/a Data Path Location C:\Documents and Settings\All Users\Documents Number of Trials Simcyp.exe No of Subjects per Trial File Version 10, 12, 0, 95 Population name Healthy Volunteers Date Modified 14/01/2011 Minimum Age (years) File Size (bytes) Maximum Age (years) SimDB.dll Propn. of Females File Version 10, 0, 0, 0 Fasted/Fed Fasted Date Modified 13/01/2011 Fluid intake with dose (ml) File Size (bytes) Fluid intake with dose CV (%) SimExcel.dll PK Parameters On File Version 10, 0, 0, 0 PK Profiles On Date Modified 13/01/2011 Start Day/Time Day 1, 09:00 File Size (bytes) End Day/Time Day 14, 09:00 Windows Version Version 5.1 (Build 2600: Service Pack 3) Study Duration (h) Excel Version 2007 SimPaediatric.dll Sub : Route Oral File Version 10, 0, 0, 1 Sub : Dose Units Dose (mg) Date Modified 13/01/2011 Sub : Dose File Size (bytes) Inh 1 : Route Oral Simulation Duration(seconds) Inh 1 : Dose Units Dose (mg) Inh 1 : Dose Seed Fixed Seed Value Output sampling interval (h) Memory Size Number of time samples Solubility Cap (mg/ml) Differential Solver 5th-order Runge-Kutta Maximum number of steps Relative Tolerance Relative Tolerance when ADAM is used Integration error tolerance Paediatric Module Not Loaded
5 Supplemental Table 2 (page 4 of 8) Input parameters for Simulation with KI = 1.7 µm
6 Supplemental Table 2 (page 5 of 8) Simcyp Population Based Sim 6/21/ :56 Simcyp : Version SP1 SE(14/0 Substrate Inhibitor 1 Compound Name Sim-S-Mephenytoin Compound Name Omeprazole with MBI Route Oral Route Oral Sub : Dose Units Dose (mg) Inh 1 : Dose Units Dose (mg) Sub : Dose Inh 1 : Dose Start Day Start Day Start Time 9h0m Start Time 9h0m Dosing Regime Single Dose Dosing Regime Multiple Dose Dose Interval (h) PhysChem and Blood Binding Number of Doses Mol Weight (g/mol) PhysChem and Blood Binding log P Compound Type Monoprotic Base Mol Weight (g/mol) pka log P B/P Compound Type Ampholyte Haematocrit pka fu Input User Input pka fu B/P Protein Reference Haematocrit Main Plasma Binding Protein HSA fu Input User Input fu Absorption Protein Reference Main Plasma Binding Protein HSA Absorption Model 1st order Input Type Entered Absorption fa CV fa (%) Absorption Model 1st order ka (1/h) Input Type Entered CV ka (%) fa fu(gut) CV fa (%) Q(Gut) Input Predicted ka (1/h) Q(Gut) (L/h) CV ka (%) Peff,man Type Predicted fu(gut) Permeability Assay Physicochemical Q(Gut) Input Predicted PSA(Ų) Q(Gut) (L/h) HBD Peff,man Type Predicted Permeability Assay MDCK Distribution MDCK(10E-06 cm/s) Reference Compound Multiple Distribution Model Minimal PBPK Model Reference Compound Value (10E-06 cm/s) Vss mode Entered Scalar Vss (L/kg) CV Vss (%) Distribution Elimination Distribution Model Minimal PBPK Model Vss mode Entered Vss (L/kg) Allometric Scaling Not Used CV Vss (%) Clearance Type Enzyme Kinetics Elimination Ontogeny Profile No Profile Used In vitro metabolic system HLM Use Allelic variants for CYP2C9 No Allometric Scaling Not Used Pathway N-demethylation Clearance Type Enzyme Kinetics Enzyme CYP2B6 Ontogeny Profile No Profile Used Vmax In vitro metabolic system Recombinant Km Use Allelic variants for CYP2C9 No fu mic Pathway 5-OH Pathway 4-OH Enzyme CYP2C19 Enzyme CYP2C19 Vmax 6.470
7 Supplemental Table 2 (page 6 of 8) Vmax Km Km fu mic fu mic Pathway 5-OH Additional Hep Ontogeny Profile No Profile Used Enzyme CYP3A4 Biliary CLint (Hep)(µL/min/10^6) Vmax CV Biliary CLint (Hep)(%) Km Active Uptake into Hepatocyte fu mic CL R (L/h) Additional Systemic Clearance CV (%) Pathway Sulfoxidation Enzyme CYP3A4 Vmax Km fu mic Additional Hep Ontogeny Profile No Profile Used Biliary CLint (Hep)(µL/min/10^6) CV Biliary CLint (Hep)(%) Active Uptake into Hepatocyte CL R (L/h) Additional Systemic Clearance CV (%) CYPs Interaction Enzyme CYP2C19 Ki (µm) fu mic MBI Kapp (µm) MBI Kinact (1/h) MBI fu mic 0.750
8 Supplemental Table 2 (page 7 of 8) mulator 01/2011) Trial Design Software Version Detail Use Pop Representative Yes Source File Location C:\Program Files\Simcyp\Simcyp Simulator v10 Population Size n/a Data Path Location C:\Documents and Settings\All Users\Documents Number of Trials Simcyp.exe No of Subjects per Trial File Version 10, 12, 0, 95 Population name Healthy Volunteers Date Modified 14/01/2011 Minimum Age (years) File Size (bytes) Maximum Age (years) SimDB.dll Propn. of Females File Version 10, 0, 0, 0 Fasted/Fed Fasted Date Modified 13/01/2011 Fluid intake with dose (ml) File Size (bytes) Fluid intake with dose CV (%) SimExcel.dll PK Parameters On File Version 10, 0, 0, 0 PK Profiles On Date Modified 13/01/2011 Start Day/Time Day 1, 09:00 File Size (bytes) End Day/Time Day 14, 09:00 Windows Version Version 5.1 (Build 2600: Service Pack 3) Study Duration (h) Excel Version 2007 SimPaediatric.dll Sub : Route Oral File Version 10, 0, 0, 1 Sub : Dose Units Dose (mg) Date Modified 13/01/2011 Sub : Dose File Size (bytes) Inh 1 : Route Oral Simulation Duration(seconds) Inh 1 : Dose Units Dose (mg) Inh 1 : Dose Seed Fixed Seed Value Output sampling interval (h) Memory Size Number of time samples Solubility Cap (mg/ml) Differential Solver 5th-order Runge-Kutta Maximum number of steps Relative Tolerance Relative Tolerance when ADAM is used Integration error tolerance Paediatric Module Not Loaded
9 Supplemental Table 2 (page 8 of 8) Input parameters for Simulation with KI = 9.1 µm
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The Proton Pump Inhibitor, Omeprazole, but not Lansoprazole or. Pantoprazole, is a Metabolism-Dependent Inhibitor of CYP2C19:
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