TABLE 2

PBPK model input parameters

Parameter	Description	Unit	Parameter Value
Parameter	Description	Unit	Benzydamine	Itopride	Tozasertib	Tamoxifen	Moclobemide	Imipramine	Clozapine	Olanzapine	Ranitidine
Physicochemical data^{^a}			309.4	358.4	464.6	371.5	268.7	280.4	326.8	312.4	314.4
MW	Molecule weight	g/mol
log P/log D	Octanol: buffer partition coefficient		4.24/2.34	2.12/0.72	4.3/3.36	6.8/4.62	2.17/1.65	5.03/2.51	3.5/2.96	3.5/2.15	0.67/−0.78
pK_a/type	Dissociation constant		9.3/base	8.8/base	8.3/base	8.8/base	6/base	9.4/base	7.75/base	7.2/base	8.2/2.7 diprotic base
BP	Blood-to-plasma partition ratio		0.76	0.72	0.94	0.89	0.84	0.93	0.825	0.73	0.90
F_u	Fraction unbound in plasma		0.146	0.262	0.0873	0.00035	0.638	0.261	0.0925	0.327	0.912
Absorption
K_a	Absorption rate constant	1/h	1.21	4, lag time of 0.4 hours	—	0.39	1.12	1	2.2.2	1.36	0.38
F_u,gut	Unbound fraction of drug in gut enterocytes. Either default of 1 or predicted value used		1	0.192	1	1	1	1	1	1	1
P_caco-2	Caco-2 permeability	× 10⁻⁶ cm/s	Mech-eff model	—	—	Mech-eff model	64.4	Mech-eff model	PSA/HBD	PSA/HBD	PSA/HBD
P_eff,man	Human jejunum permeability	× 10⁻⁴ cm/s	8.71	5	—	4.09	6.95	8.56	7.87	7.83	0.94
Distribution
V_ss	Distribution volume at steady-state after IV or predicted using Method 2	l/kg	0.966	6.3	5.6	15.7	3.59	17.1	1.6	5.1	1.50
V_ss	Distribution model	l/kg	Minimal PBPK model	Full PBPK	Full PBPK	Full PBPK	Full PBPK	Minimal PBPK	Minimal PBPK	Minimal PBPK	Full PBPK
Elimination
CL_int-HLM	Human liver microsomal protein in vitro intrinsic clearance	µl/min/mg protein	18	18	61	4	3	14	18	<3	<3
CL_int- Hepatocytes	Hepatocytes in vitro intrinsic clearance	µl/min per 10⁶ cells	9	11	29	4	3	9	5	2	0.6
F_m (% FMO)	Fraction metabolized contribution	%	53	96	38	28	38	21	23	23	26
CL_int - rFMO	FMO 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 known	µl/min/pmol protein or µl/min/mg protein for HLM	FMO1 = 0.44,FMO3 = 0.29,FMO5 = 0.001,CYP2D6 = 8.5	FMO1 = 0.79,FMO3 = 0.118,FMO5 = 0.0.052,CYP3A4 = 0.87	FMO1 = 0.24,FMO3 = 0.48,FMO5 = 0,CYP3A4 = 39	FMO1 = 0.083,FMO3 = 0,FMO5 = 0,CYP3A4 = 3.6	FMO1 = 0.018,FMO3 = 0.031,FMO5 = 0.003,CYP3A4 = 2.9	FMO1 = 0.163,FMO3 = 0.013, FMO5 = 0.001,CYP1A2 = 0.058,2C19 = 2.36,2D6 = 47,3A4 = 0.021,Additional HLM CL = 1.52	FMO1 = 0.031,FMO3 = 0,FMO5 = 0,CYP3A4 = 11.1	FMO1 = 0.04,FMO3 = 0.006,FMO5 = 0,CYP3A4 = 2.31	FMO1 = 0.011,FMO3 = 0.003,FMO5 = 0.028,CYP3A4 = 2.22
Systemic clearance	Systemic absolute CL or oral CL	l/h	9.66^{^b}	88^{^c}	87^{^b}	8^{^c}	63.7^{^b}	54^{^c}	32^{^c}	26^{^c}	7.56^{^b}
Renal clearance	Renal CL	l/h	0.24	1.5	—	—	—	—	—	—	24.6
F_u,mic	Unfound fraction in microsomes		0.35	1.05	0.18	0.02	0.98	0.31	0.30	0.73	0.97
F_u,inc	Unfound fraction in hepatocytes		0.74	0.88	0.21	0.003	0.87	0.65	0.33	0.86	0.98

HBD, hydrogen bond donor; PSA, polar surface area; rCYP, recombinant cytochrome P450; V_ss, 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.