TABLE 2

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.	Compound	fu,p		Rb		fu(inc)^{^a}	In vitro				In vivo
						fu(inc)^{^a}	CLint,h (hep sus)	CLint,h,u	CLint,h (Hepato Pac)	CLint,h,u	CLint,h,u	CLh,p	CLr,p	CLothers,p	CLtot,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 2^{^b}
1	Midazolam	0.0320	Simcyp	0.60	Simcyp	0.25	32.50	345.35	43.60	463.29	631.27	8.27	0.02	0.00	8.29
2	Quinidine	0.2020	Simcyp	0.82	Simcyp	0.72	2.59	9.54	12.50	46.04	52.34	6.80	1.67	0.00	8.47
3	Dextromethorphan	0.5000	Simcyp	1.32	Simcyp	0.91	9.60	27.88	13.70	39.78	57.00	14.76	0.00	0.00	14.76
4	Diclofenac	0.0038	Ye et al., 2016	0.55	Ye et al., 2016	0.04	3.10	222.73	4.30	308.95	561.90	1.83	2.74	0.00	4.57
5	Tolbutamide	0.0440	Simcyp	0.60	Simcyp	0.32	1.17	9.80	1.30	10.89	4.85	0.21	0.00	0.00	0.21
6	Bupropion	0.1600	Simcyp	0.82	Simcyp	0.66	0.70	2.82	27.10	109.10	119.20	9.52	0.00	0.00	9.52
7	Propranolol	0.0990	Poulin and Theil, 2002	0.89	Shibata et al., 2002	0.52	3.00	15.13	11.50	57.99	129.88	7.92	0.04	0.00	7.96
8	Verapamil	0.1000	Lombardo et al., 2004	0.77	Shibata et al., 2002	0.53	23.40	117.37	23.40	117.37	12,484.95	17.61	0.36	0.00	17.97
9	Clozapine	0.0550	Simcyp	0.85	Simcyp	0.37	5.00	35.88	12.90	92.57	43.40	2.13	0.0065	0.00	2.13
10	Efavirenz	0.0290	Simcyp	0.74	Simcyp	0.23	2.60	29.85	2.40	27.55	21.92	0.61	0.00	0.00	0.61
11	Rosiglitazone	0.0030	Simcyp	0.96	Simcyp	0.03	2.77	250.34	3.00	271.13	245.70	0.71	0.0007	0.00	0.71
12	Omeprazole	0.0430	Simcyp	0.59	Simcyp	0.31	6.30	53.65	25.60	218.00	90.69	3.04	0.01	0.00	3.04
13	Ethinylestradiol	0.0150	Simcyp	1.00	Simcyp	0.13	37.92	757.49	17.90	357.57	403.36	4.80	1.0011	0.00	5.80
14	Mycophenolic acid	0.0300	Bullingham et al., 1998	0.70	Malmborg and Ploeger, 2013	0.24	5.38	60.13	18.00	201.17	209.22	4.53	0.0158	0.00	4.54
15	Clopidogrel	0.0370	In silico pred.	1.00	-^{^c}	0.28	200.00	1902.23	59.60	566.86	1229.14	15.36	0.00	0.00	15.36
19	Benzydamine	0.1460	Reddy et al., 2018	0.76	Reddy et al., 2018	0.63	2.63	11.00	5.50	23.01	7.04	0.97	1.31	0.00	2.29
20	Cyclosporine A	0.0365	Simcyp	1.62	Simcyp	0.27	3.10	29.79	10.30	98.97	460.25	11.61	0.01	0.00	11.62
21	Ketoconazole	0.0290	Simcyp	0.62	Simcyp	0.23	23.50	269.77	28.40	326.02	108.50	2.58	0.04	0.00	2.62
24	Simvastatin	0.0200	Simcyp	1.00	Simcyp	0.17	88.84	1383.77	49.70	774.13	422.83	6.20	0.92	0.00	7.12
28	Gemfibrozil	0.0080	Simcyp	0.75	Simcyp	0.07	2.34	82.78	8.10	286.55	159.50	1.19	0.01	0.09^{^d}	1.28
30	Memantine	0.5500	Product monograph_Lundbeck	1.00	-^{^c}	0.92	Not detected	0.00	0.50	1.43	0.71	0.39	1.82	0.00	2.20
35	Digoxin	0.7100	Simcyp	1.07	Simcyp	0.96		0.00	0.70	1.92	1.97	1.32	2.48	0.00	3.80
ECCS class 3b^{^e}
22	Atorvastatin	0.0570	Waldmeier et al., 1997	0.68	PMDA database	0.38	1.29	9.04	9.90	69.38	179.64	6.21	0.00	0.55	6.75^{^f}
23	Fluvastatin	0.0100	Tse et al., 1993	0.71	Tse et al., 1993	0.09	Not detected	0.00	19.20	552.50	401.46	3.23	0.33	2.54	6.10^{^f}
25	Pravastatin	0.4850	Simcyp	0.56	Simcyp	0.90	1.00	2.92	0.40	1.17	22.15	5.86	4.60	0.00	10.47
26	Rosuvastatin	0.1070	Simcyp	0.63	Simcyp	0.55	1.24	6.01	1.20	5.81	186.86	8.40	3.24	0.00	11.64
29	Fexofenadine	0.3000	Product monograph_Sanofi (a median of the range; in vivo fu,p)	1.00	-^{^c}	0.81	Not detected	0.00	0.10	0.33	8.04	2.19	0.91	0.00	3.10
31	Repaglinide	0.0230	Simcyp	0.62	Simcyp	0.19	3.38	46.83	8.80	121.92	1057.47	9.04	0.01	0.00	9.05
33	Valsartan	0.0560	Simcyp	0.56	Simcyp	0.37	0.30	2.13	0.40	2.84	6.87	0.37	0.15	0.00	0.52
ECCS class 3a and 4^{^g}
16	Oseltamivir (prodrug)	0.8130	In silico pred.	1.00	-^{^c}	0.98	25.72	69.46	19.50	52.66	204.91	20.36	6.17	0.00	26.53
17	Irinotecan	0.2980	Toshimoto et al., 2017	0.97	Toshimoto et al., 2017	0.81	0.80	2.61	3.30	10.76	32.01	6.70^{^h}	1.87	0.00	8.57
18	SN-38	0.0283	Toshimoto et al., 2017	1.31	Toshimoto et al., 2017	0.23	0.50	5.85	6.60	77.25	264.80^{^h}	—	—	—	—
27	Famotidine	0.8105	(Echizen and Ishizaki, 1991) (a median of the range; in vivo fp)	1.00	-^{^c}	0.98	Not detected	0.00	Not detected	0.00	1.82	1.38	3.63	0.00	5.01
32	Furosemide	0.0240	Camenisch and Umehara, 2012	0.75	Camenisch and Umehara, 2012	0.20	Not detected	0.00	0.00	0.00	8.31	0.20	0.71	1.06^ⁱ	1.97
34	Cimetidine	0.7785	(Somogyi and Gugler, 1983) (mean of the range)	0.98	Somogyi and Gugler, 1983	0.97	Not detected	0.00	0.50	1.36	6.09	3.92	6.81	0.00	10.74
36	Talinolol	0.3000	Thiel et al., 2015	1.00	-^{^c}	0.81	1.00	3.26	4.50	14.65	7.70	2.10	2.80	0.00	4.90

↵^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.