Table 3

PBPK models and model details for recognized P450 inhibitors

Enzyme Inhibited	Compound	Application	Minimal or Full PBPK	Oral or IV	Clearance^{^a}	Additional Inhibition Parameters	Simulated genotype specified?	Population matched?^{^b}	Verification^{^c}	Acceptance Criteria^{^d}	Software	Citation
Strong Inhibitors
CYP2C8	Gemfibrozil	DDI	Minimal	Oral	PE	CYP3A4	No	N.S.	A, B, E	1	Napp	(Kudo et al., 2013)
CYP2D6	Paroxetine	Pregnancy	Full	Oral	In vitro	CYP3A4	Yes	Sex, PGX	D, E	2	Simcyp, Matlab	(Ke et al., 2013b)
	Fluoxetine	DDI	Minimal	Oral	In vitro	CYP1A2	Yes	N.S.	E	1	Simcyp	(Siccardi et al., 2013)
						CYP2C9
						CYP2C19
CYP3A4	Clarithromycin	DDI	Minimal	Oral	In vivo	—	Yes	Age, Sex, PGX	A, B, E	3	Simcyp	(Wang, 2010)
	Clarithromycin	DDI	Minimal	Oral	In vivo	—	No	Age, Sex, PGX	B, E	3	Simcyp	(Xu et al., 2009)
	Itraconazole	DDI	Minimal	Oral	PE	—	No	N.S.	A, B, E	1	Napp	(Kudo et al., 2013)
	Ritonavir	DDI	Minimal	Oral	In vitro	CYP2C9	Yes	N.S.	A, E	1	Simcyp	(Siccardi et al., 2013)
	Ritonavir	DDI	Minimal	Oral	In vitro	CYP2D6	Yes	N.S.	A, E	1	Simcyp	(Siccardi et al., 2013)
	Ritonavir	Clinical PK	Minimal	Oral	In vitro	CYP3A5	Yes	N.S.	D	1	Simcyp	(Kaspera et al., 2014)
						CYP2D6
						CYP2J2
	Telithromycin	RI	Full	Oral	BC	P-gp	Yes	N.S.	D, E	1	Simcyp	(Zhao et al., 2012a)
	Telithromycin	DDI	Full	Oral	BC	P-gp	No	N.S.	A, B, E	1	Simcyp	(Vieira et al., 2012)
	Telithromycin	DDI	Full	Oral	BC	CYP3A5	No	N.S.	A, B, E	1	Simcyp	(Vieira et al., 2012)
Moderate Inhibitors
CYP2C9	Amiodarone	DDI	Full	Both	BC	CYP2D6	No	N.S.	A, E	1	Simcyp	(Chen et al., 2015)
CYP2C9	Amiodarone	DDI	Full	Both	BC	CYP3A4	No	N.S.	A, E	1	Simcyp	(Chen et al., 2015)
CYP2C19	Omeprazole	Clinical PK	Minimal	Both	BC	—	Yes	PGX	B, D, E	1	Simcyp	(Wu et al., 2014)
CYP3A4	Diltiazem	DDI	Minimal	Oral	In vivo	—	No	Age, Sex, PGX	B, E	3	Simcyp	(Xu et al., 2009)
	Diltiazem	DDI	Minimal	Oral	In vitro	—	No	N.S.	A, B, E	1	WinNonlin	(Zhang et al., 2009)
	Diltiazem	DDI	Minimal	Oral	In vivo	CYP2D6	No	Age, Sex	B	1	Simcyp	(Friedman et al., 2011)
	Erythromycin	DDI	Minimal	Oral	In vivo	CYP2C8	No	Age, Sex, PGX	B, E	3	Simcyp	(Xu et al., 2009)
	Verapamil	DDI	Minimal	Oral	In vitro	CYP2C8	No	N.S.	A, B, C, E	5	WinNonlin	(Wang et al., 2013a)
	Verapamil	DDI	Minimal	Oral	In vitro	OATP1B1	No	N.S.	A, B, C, E	5	WinNonlin	(Wang et al., 2013a)
	Verapamil	DDI	Full	Oral	BC	—	No	Age, Sex	A, E	1	Simcyp	(Neuhoff et al., 2013a)
	Verapamil	DDI	Minimal	Oral	In vivo	—	No	Age, Sex, PGX	B, E	3	Simcyp	(Xu et al., 2009)
Weak Inhibitors
CYP2C8	Trimethoprim	DDI	Minimal	Oral	In vivo	—	Yes	N.S.	B, E	1	Simcyp	(Yeo et al., 2013)

↵^a PE = parameter estimation from in vivo data, BC = back-calculated from in vivo data.
↵^b PGX = genotype, N.S. = not specified.
↵^c Data sets used in model verification included: (A) Single dose PK, (B) alternative dosing regimen, (C) alternative formulation, (D) alternative population, (E) DDI.
↵^d Acceptance criteria fell into 5 categories: (1) Not specified, (2) Ratio of PK parameter(s) must be within 30% of observed ratio, (3) Ratio of PK parameter(s) must be within 2 fold of observed ratio, (4) PK parameters must be within 30% of observed parameters, (5) PK parameters must be within 2 fold of observed parameters.