Table 1

Summary of PBPK models published for P450 Sensitive Substrates

Main Clearance Enzyme	Compound	Application	Minimal or Full PBPK	Oral or IV	Clearance^{^a}	Simulated genotype specified?	Population matched?^{^b}	Verification^{^c}	Acceptance Criteria^{^d}	Software	Citation
CYP1A2	Caffeine	Allometry	Full	Oral	SF	No	N.S	A,D	1	PK Sim	(Thiel et al., 2014)
CYP2B6	Efavirenz	DDI	Minimal	Oral	In vitro	Yes	N.S	A, E	1	Simcyp	(Siccardi et al., 2013)
	Efavirenz	DDI	Full	Oral	In vitro	Yes	Sex	D,E	1	Simcyp	(Rekic et al., 2011)
	Efavirenz	Absorption	Full	Oral	In vitro	No	N.S	B	5	Matlab	(Rajoli et al., 2014)
CYP2C8	Repaglinide	Diabetes	Full	Oral	In vitro	No	N.S.	B,D	3	WinNonlin	(Li et al., 2014b)
	Repaglinide	RI	Full	Oral	BC	Yes	N.S.	D	1	Simcyp	(Zhao et al., 2012a)
	Repaglinide	DDI	Minimal	Oral	PE	No	N.S	B, E	1	Napp	(Kudo et al., 2013)
	Repaglinide	DDI	Full	Oral	BC	No	N.S	C,E	1	Simcyp	(Varma et al., 2013)
CYP2C19	Clobazam	Pediatrics	Full	Oral	In vitro	No	N.S.	B,D,E	1	Matlab	(Ogungbenro and Aarons, 2015)
CYP2C19	Omeprazole	Clinical PK	Minimal	Both	BC	Yes	N.S.	B,E	1	Simcyp	(Wu et al., 2014)
CYP2D6	Metoprolol	Pregnancy	Full	Oral	In vitro, SF	Yes	Sex, PGX	D, E	2	Simcyp, Matlab	(Ke et al., 2013b)
	Dextromethorphan	Pregnancy	Full	Oral	PE	No	Sex, PGX	D, E	2	Simcyp, Matlab	(Ke et al., 2013b)
	Dextromethorphan	Allometry	Full	Oral	SF	No	N.S	A,D	1	PK Sim	(Thiel et al., 2014)
CYP3A4	Alfentanil	DDI	Full	Oral	BC	No	N.S.	C, E	5	Gastroplus	(Baneyx et al., 2014)
	Alfentanil	DDI	Full	Oral	In vitro	No	N.S.	E	5	WinNonlin	(Guo et al., 2013)
	Buspirone	DDI	Full	Oral	In vitro	No	N.S.	E	5	WinNonlin	(Guo et al., 2013)
	Indinavir	Pregnancy	Full	Both	In vitro, SA	No	Sex	C, D, E	2	Simcyp, Matlab	(Ke et al., 2012)
	Maraviroc	DDI	Minimal	Oral	In vitro	No	N.S.	A,E	1	Simcyp	(Hyland et al., 2008)
	Midazolam	Pregnancy	Full	Oral	In vitro	No	Sex	A, D	2	Simcyp, Matlab	(Ke et al., 2012)
	Midazolam	DDI	Full	Oral	BC	No	N.S	C, D	5	Gastroplus	(Baneyx et al., 2014)
	Midazolam	DDI	Full	Oral	PE	No	N.S	A	4	Berkeley Madonna	(Brantley et al., 2014)
	Midazolam	Pregnancy	Full	Oral	In vivo	No	Sex	B,D	3	Gastroplus	(Xia et al., 2013b)
	Midazolam	DDI	Minimal	Oral	In vitro	No	N.S.	E	5	WinNonlin	(Wang et al., 2013a)
	Midazolam	DDI	Full	Oral	In vitro	No	N.S.	E	5	WinNonlin	(Guo et al., 2013)
	Midazolam	Allometry	Full	Oral	SF	No	N.S	A, D	1	PK Sim	(Thiel et al., 2014)
	Quetiapine	Pediatrics	Both	Oral	BC	No	Age, Sex	D, E	1	Simcyp	(Johnson et al., 2014)
	Sildenafil	RI	Full	Oral	BC	Yes	N.S.	D	2	Simcyp	(Zhao et al., 2012a)
	Simvastain	DDI	Full	Oral	In vitro	No	N.S.	E	5	WinNonlin	(Guo et al., 2013)
	Simvastatin	DDI	Minimal	Oral	In vitro	No	N.S.	A, E	5	WinNonlin	(Wang et al., 2013a)
	Triazolam	DDI	Full	Oral	In vitro	No	N.S.	E	5	WinNonlin	(Guo et al., 2013)
	Triazolam	DDI	Full	Oral	BC	No	N.S.	C, E	5	Gastroplus	(Baneyx et al., 2014)

↵^a BC = back-calculated from in vivo data, PE = parameter estimate, SA = sensitivity analysis, SF = scaling factor from mice.
↵^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.