Table 1

Summary of PBPK models published for P450 Sensitive Substrates

Main Clearance EnzymeCompoundApplicationMinimal or Full PBPKOral or IVClearanceaSimulated genotype specified?Population matched?bVerificationcAcceptance CriteriadSoftwareCitation
CYP1A2CaffeineAllometryFullOralSFNoN.SA,D1PK Sim(Thiel et al., 2014)
CYP2B6EfavirenzDDIMinimalOralIn vitroYesN.SA, E1Simcyp(Siccardi et al., 2013)
EfavirenzDDIFullOralIn vitroYesSexD,E1Simcyp(Rekic et al., 2011)
EfavirenzAbsorptionFullOralIn vitroNoN.SB5Matlab(Rajoli et al., 2014)
CYP2C8RepaglinideDiabetesFullOralIn vitroNoN.S.B,D3WinNonlin(Li et al., 2014b)
RepaglinideRIFullOralBCYesN.S.D1Simcyp(Zhao et al., 2012a)
RepaglinideDDIMinimalOralPENoN.SB, E1Napp(Kudo et al., 2013)
RepaglinideDDIFullOralBCNoN.SC,E1Simcyp(Varma et al., 2013)
CYP2C19ClobazamPediatricsFullOralIn vitroNoN.S.B,D,E1Matlab(Ogungbenro and Aarons, 2015)
OmeprazoleClinical PKMinimalBothBCYesN.S.B,E1Simcyp(Wu et al., 2014)
CYP2D6MetoprololPregnancyFullOralIn vitro, SFYesSex, PGXD, E2Simcyp, Matlab(Ke et al., 2013b)
DextromethorphanPregnancyFullOralPENoSex, PGXD, E2Simcyp, Matlab(Ke et al., 2013b)
DextromethorphanAllometryFullOralSFNoN.SA,D1PK Sim(Thiel et al., 2014)
CYP3A4AlfentanilDDIFullOralBCNoN.S.C, E5Gastroplus(Baneyx et al., 2014)
AlfentanilDDIFullOralIn vitroNoN.S.E5WinNonlin(Guo et al., 2013)
BuspironeDDIFullOralIn vitroNoN.S.E5WinNonlin(Guo et al., 2013)
IndinavirPregnancyFullBothIn vitro, SANoSexC, D, E2Simcyp, Matlab(Ke et al., 2012)
MaravirocDDIMinimalOralIn vitroNoN.S.A,E1Simcyp(Hyland et al., 2008)
MidazolamPregnancyFullOralIn vitroNoSexA, D2Simcyp, Matlab(Ke et al., 2012)
MidazolamDDIFullOralBCNoN.SC, D5Gastroplus(Baneyx et al., 2014)
MidazolamDDIFullOralPENoN.SA4Berkeley Madonna(Brantley et al., 2014)
MidazolamPregnancyFullOralIn vivoNoSexB,D3Gastroplus(Xia et al., 2013b)
MidazolamDDIMinimalOralIn vitroNoN.S.E5WinNonlin(Wang et al., 2013a)
MidazolamDDIFullOralIn vitroNoN.S.E5WinNonlin(Guo et al., 2013)
MidazolamAllometryFullOralSFNoN.SA, D1PK Sim(Thiel et al., 2014)
QuetiapinePediatricsBothOralBCNoAge, SexD, E1Simcyp(Johnson et al., 2014)
SildenafilRIFullOralBCYesN.S.D2Simcyp(Zhao et al., 2012a)
SimvastainDDIFullOralIn vitroNoN.S.E5WinNonlin(Guo et al., 2013)
SimvastatinDDIMinimalOralIn vitroNoN.S.A, E5WinNonlin(Wang et al., 2013a)
TriazolamDDIFullOralIn vitroNoN.S.E5WinNonlin(Guo et al., 2013)
TriazolamDDIFullOralBCNoN.S.C, E5Gastroplus(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.