TABLE 2

Summary of the 54 clinical studies and predictions based on Simcyp time-based model and static model

Values highlighted in bold had an absolute difference between the predicted and observed AUC changes >2.

InhibitorDosePretreatment DurationSubstrateDoseDosing DayMean AUC RatioReferences
ObservedSimcypStatic Model: kdeg 0.03
kdeg 0.0077kdeg 0.03
mgmg or mg/kgafold
Clarithromycinb500b.i.d. for 2 days 4 dosesTriazolam0.125Day 2, 3rd dose5.113.06.88.9Greenblatt et al., 1998
Clarithromycinc500b.i.d. for 7 daysMidazolam i.v.0.05Day 72.56.63.75.3Wang et al., 2004a
Clarithromycinc500b.i.d. for 7 daysMidazolam i.v.0.05Day 91.62.81.41.5Wang et al., 2004a
Clarithromycinc500b.i.d. for 7 daysMidazolam i.v.0.05Day 111.01.81.11.1Wang et al., 2004a
Clarithromycinc500b.i.d. for 7 daysMidazolam i.v.0.05Day 141.01.31.01.0Wang et al., 2004a
Clarithromycinc500b.i.d. for 7 daysMidazolam4Day 78.015.88.39.2Wang et al., 2004a
Clarithromycinc500b.i.d. for 7 daysMidazolam4Day 92.74.72.11.9Wang et al., 2004a
Clarithromycinc500b.i.d. for 7 daysMidazolam4Day 111.22.41.31.2Wang et al., 2004a
Clarithromycinc500b.i.d. for 7 daysMidazolam4Day 140.91.61.11.0Wang et al., 2004a
Clarithromycinb500b.i.d. for 7 daysMidazolam8Day 78.416.28.99.2Gurley et al., 2006
Clarithromycinb500b.i.d. for 7 daysMidazolam8Day 75.516.19.29.2Gurley et al., 2008
Clarithromycinb500Single doseSildenafil502 h after2.34.33.49.3Hedaya et al., 2006
Clarithromycinb5004 doses for 2 daysZolpidem5Day 2, 3rd dose1.01.81.71.9Farkas et al., 2009
Clarithromycinb,d500b.i.d. for 9 daysSimvastatin40Day 810.031.321.27.9Jacobson, 2004
Diltiazem IRb30t.i.d. for 3 days, 10 dosesNifedipine20Day 4, 10th dose2.23.22.02.8Tateishi et al., 1989
Diltiazem IRb90t.i.d. for 3 days, 10 dosesNifedipine20Day 4, 10th dose3.18.03.64.6Tateishi et al., 1989
Diltiazem IRb601 doseNifedipine20Day 11.31.41.42.3Ohashi et al., 1993
Diltiazem IRb60t.i.d. for 3 days, 10 dosesNifedipine20Day 4, 10th dose2.46.33.12.9Ohashi et al., 1993
Diltiazem IRb60t.i.d. for 6 days, 19 dosesNifedipine20Day 7, 19th dose3.06.33.02.9Ohashi et al., 1993
Diltiazem IRb60t.i.d. for 2 daysTriazolam0.25D2, 5th dose3.43.92.53.0Varhe et al., 1996
Diltiazem IRb60t.i.d. for 3 days, 10 dosesTriazolam0.25Day 4, 10th dose2.33.92.13.0Kosuge et al., 1997
Diltiazem IRb60t.i.d. for 2 days, 5 dosesMidazolam15Day 2, 4th dose3.83.52.63.9Backman et al., 1994
Diltiazem SRe120b.i.d. for 14 days, 28 dosesSimvastatin20Day14,27th dose4.82011.64.9Mousa et al., 2000
Diltiazem SRe120b.i.d. for 6 days, 6 dosesMidazolam4Day 64.010.55.15.7Zhang et al., 2009
Diltiazem SRe120b.i.d. for 6 days, 6 dosesMidazolam i.v.0.05Day 61.74.02.23.3Zhang et al., 2009
Diltiazem SRb,d240q.d. for 2 daysMidazolam2Day 23.34.93.45.2f
Diltiazem SRb,d240q.d. for 5 daysMidazolam2Day 53.35.93.35.2f
Erythromycinc,d500b.i.d. for 5 daysSildenafil100Day 52.84.02.63.2Muirhead et al., 2002
Erythromycinc400t.i.d. for 10 daysAlprazolam0.8Day 82.53.62.22.1Yasui et al., 1996
Erythromycinb5004 doses for 2 daysTriazolam0.125Day 2, 3rd dose3.72.41.92.3Greenblatt et al., 1998
Erythromycinb200q.i.d. for 2 daysMidazolam5Day 2, 5th dose2.32.21.92.3Okudaira et al., 2007
Erythromycinb200q.i.d. for 4 daysMidazolam5Day 4, 13th dose3.44.22.52.3Okudaira et al., 2007
Erythromycinb200q.i.d. for 7 daysMidazolam5Day 7, 19th dose3.45.62.62.3Okudaira et al., 2007
Erythromycinb500t.i.d. for 6 daysMidazolam15Day 64.48.23.93.3Olkkola et al., 1993
Erythromycinb500t.i.d. for 6 daysMidazolam i.v.0.05Day 62.21.60.92.0Olkkola et al., 1993
Erythromycinb500t.i.d. for 5 daysMidazolam15Day 5, 13th dose3.89.04.03.3Yeates et al., 1996
Erythromycinb500t.i.d. for 2 daysSimvastatin40Day 2, 4th dose6.27.85.93.3Kantola et al., 1998
Ritonavirb,d300–500t.i.d. for 7 daysSildenafil100Day 711.02.810.517.8Muirhead et al., 2000
Ritonavirb2004 doses for 2 daysAlprazolam1Day 2, 2nd dose2.51.87.09.9Greenblatt et al., 2000a
Ritonavirb2004 doses for 2 daysTriazolam0.125Day 2, 3rd dose20.43.019.813.0Greenblatt et al., 2000b
Ritonavirb2004 doses for 2 daysZolpidem5Day 2, 3rd dose1.32.02.12.0Greenblatt et al., 2000b
Saquinavirc,d1200t.i.d. for 7 daysSildenafil100Day 73.11.06.311.7Muirhead et al., 2000
Saquinavirb1200t.i.d. for 4 daysMidazolam7.5Day 3, 2nd dose5.11.07.610.9Palkama et al., 1999
Saquinavirb1200t.i.d. for 4 daysMidazolam i.v.0.05Day 3, 2nd dose2.50.82.76.2Palkama et al., 1999
Verapamil IRb2 × 40t.i.d. for 2 days, 5 dosesMidazolam15Day 2, 4th dose2.94.53.13.6Backman et al., 1994
Verapamil IRb80t.i.d. for 2 daysSimvastatin40Day 2, 4th dose4.614.211.12.9Kantola et al., 1998
Verapamil SRd480q.d. for 3 daysSimvastatin40Day 44.05.63.35.7Jacobson, 2004
Verapamil SRb240q.d. for 8 daysMidazolam2Day 84.18.34.44.4Wang et al., 2005
Verapamil SRb240q.d. for 8 daysMidazolam i.v.0.05Day 82.03.42.12.5Wang et al., 2005
Fluoxetineb60 mgq.d. 5 days, 20 mg for 7 daysMidazolam10Day 120.91.01.73.2Lam et al., 2003
Fluoxetineb20q12 h for 6 daysAlprazolam1Day 3, 4th dose1.31.01.31.7Greenblatt et al., 1992
Fluoxetinec60q.d. for 8 daysTriazolam0.25Day 81.01.02.13.1Wright et al., 1992
Fluoxetineb20q.d. for 28 days, AMZolpidem10Day 28, PM1.01.01.01.4Allard et al., 1998
Fluoxetineb20q.d. for 17 days, AMZolpidem10Day 17, PM1.01.01.11.4Piergies et al., 1996
  • AM, in the morning; PM, in the evening.

  • a mg/kg for i.v. infusion.

  • b Predictions performed using Simcyp version 9.0.

  • c Predictions performed using Simcyp version 8.20, SP2.

  • d Observed and predicted AUC ratios are presented as geometric means.

  • e Predictions performed using Simcyp version 9.10.

  • f Friedman EJ, Fraser IP, Wang YH, Bergman A, Li CC, Larson P, Chodakewitz J, Wagner JA, and Stoch SA, manuscript submitted for publication.