Measured and scaled hepatic intrinsic clearance from the in vitro assays, in comparison with the respective in vivo data among 36 marketed drugs

Not detected: calculated values are below the internal resolution limit criteria (<0.1 µl/min per milligram). For IVIVE with the in vitro data, the following scaling factors were applied irrespective of differences of the two in vitro assay systems (hepatocyte suspension and HepatoPac): hepatocellularity, 120 (106 cells = mg protein/g liver); liver weight, 22 (g liver/kgbw); and body weight, 70 (kgbw). These were generally derived from a system parameter database (Johnson et al., 2005). The in vivo intrinsic hepatic clearance as reference was calculated with the well-stirred model, the in vivo CLh,p, and hepatic blood flow rate (23.2 ml/min per milligram; Johnson et al., 2005). For the marketed drugs, perfusion-limited conditions were applied even though permeability limitations in hepatic elimination may have been reported for some. Key PK parameters used to estimate the in vitro CLint,h,u (upscaled) and in vivo CLint,h,u (reference) were also provided in this table. Derivations of the in vivo CLtot,p are listed in Supplemental Table 1 with the respective literature source information. Documentation for physiologically based pharmacokinetic models for the marketed drugs are provided with the SimCYP software platform and have been verified to show good performance for prediction of PK profiles and drug-drug interaction potential. Therefore, the model input parameters and drug disposition pathways were used for the current assessment.

No.Compoundfu,pRbfu(inc)aIn vitroIn vivo
CLint,h (hep sus)CLint,h,uCLint,h (Hepato Pac)CLint,h,uCLint,h,uCLh,pCLr,pCLothers,pCLtot,p
-Ref.-Ref.-(µl/min per milligram)(ml/min per milligram)(µl/min per milligram)(ml/min per kilogram)(ml/min per kilogram
ECCS class 1a and 2b
4Diclofenac0.0038Ye et al., 20160.55Ye et al., 20160.043.10222.734.30308.95561.901.832.740.004.57
7Propranolol0.0990Poulin and Theil, 20020.89Shibata et al., 20020.523.0015.1311.5057.99129.887.920.040.007.96
8Verapamil0.1000Lombardo et al., 20040.77Shibata et al., 20020.5323.40117.3723.40117.3712,484.9517.610.360.0017.97
14Mycophenolic acid0.0300Bullingham et al., 19980.70Malmborg and Ploeger, 20130.245.3860.1318.00201.17209.224.530.01580.004.54
15Clopidogrel0.0370In silico pred.1.00-c0.28200.001902.2359.60566.861229.1415.360.000.0015.36
19Benzydamine0.1460Reddy et al., 20180.76Reddy et al., 20180.632.6311.005.5023.017.040.971.310.002.29
20Cyclosporine A0.0365Simcyp1.62Simcyp0.273.1029.7910.3098.97460.2511.610.010.0011.62
30Memantine0.5500Product monograph_Lundbeck1.00-c0.92Not detected0.000.501.430.710.391.820.002.20
ECCS class 3be
22Atorvastatin0.0570Waldmeier et al., 19970.68PMDA database0.381.299.049.9069.38179.646.210.000.556.75f
23Fluvastatin0.0100Tse et al., 19930.71Tse et al., 19930.09Not detected0.0019.20552.50401.463.230.332.546.10f
29Fexofenadine0.3000Product monograph_Sanofi (a median of the range; in vivo fu,p)1.00-c0.81Not detected0.000.100.338.042.190.910.003.10
ECCS class 3a and 4g
16Oseltamivir (prodrug)0.8130In silico pred.1.00-c0.9825.7269.4619.5052.66204.9120.366.170.0026.53
17Irinotecan0.2980Toshimoto et al., 20170.97Toshimoto et al., 20170.810.802.613.3010.7632.016.70h1.870.008.57
18SN-380.0283Toshimoto et al., 20171.31Toshimoto et al., 20170.230.505.856.6077.25264.80h
27Famotidine0.8105(Echizen and Ishizaki, 1991) (a median of the range; in vivo fp)1.00-c0.98Not detected0.00Not detected0.001.821.383.630.005.01
32Furosemide0.0240Camenisch and Umehara, 20120.75Camenisch and Umehara, 20120.20Not detected0.
34Cimetidine0.7785(Somogyi and Gugler, 1983) (mean of the range)0.98Somogyi and Gugler, 19830.97Not detected0.000.501.366.093.926.810.0010.74
36Talinolol0.3000Thiel et al., 20151.00-c0.811.003.264.5014.657.702.102.800.004.90
  • a Predicted with dilution method (Schuhmacher et al., 2000) using the respectively reported or measured unbound fractions in plasma. In hepatocyte suspension and HepatoPac assays, 10% FCS was added to the incubation media.

  • b ECCS class 1a (n = 5, in bold) and class 2 (n = 17): primarily elimination = metabolism.

  • c Informed assumption since there is no literature information available.

  • d Contribution of UGT2B7 in kidney (Simcyp).

  • e ECCS class 3b (n = 7): primarily elimination = hepatic uptake (or renal excretion).

  • f Estimation using Simcyp to capture the plasma concentration profiles over time.

  • g ECCS class 3a (n = 2, in bold) and class 4 (n = 5): primarily elimination = renal excretion.

  • h Estimation with physiologically based PK modeling using top-down approach (Toshimoto et al., 2017).

  • i Contribution of biliary excretion.