Table 1.

Summary of PBPK models published for P450 Sensitive Substrates

Main Clearance Enzyme	Compound	Application	Minimal or Full PBPK	Oral or IV	Clearancea	Simulated genotype specified?	Population matched?b	Verificationc	Acceptance Criteriad	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)
	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)

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

^bPGX = genotype, N.S. = not specified.

^cData sets used in model verification included: (A) Single dose PK, (B) alternative dosing regimen, (C) alternative formulation, (D) alternative population, (E) DDI.

^dAcceptance 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.