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.
| Inhibitor | Dose | Pretreatment Duration | Substrate | Dose | Dosing Day | Mean AUC Ratio | References | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Observed | Simcyp | Static Model: kdeg 0.03 | ||||||||
| kdeg 0.0077 | kdeg 0.03 | |||||||||
| mg | mg or mg/kga | fold | ||||||||
| Clarithromycinb | 500 | b.i.d. for 2 days 4 doses | Triazolam | 0.125 | Day 2, 3rd dose | 5.1 | 13.0 | 6.8 | 8.9 | Greenblatt et al., 1998 |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam i.v. | 0.05 | Day 7 | 2.5 | 6.6 | 3.7 | 5.3 | Wang et al., 2004a |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam i.v. | 0.05 | Day 9 | 1.6 | 2.8 | 1.4 | 1.5 | Wang et al., 2004a |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam i.v. | 0.05 | Day 11 | 1.0 | 1.8 | 1.1 | 1.1 | Wang et al., 2004a |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam i.v. | 0.05 | Day 14 | 1.0 | 1.3 | 1.0 | 1.0 | Wang et al., 2004a |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam | 4 | Day 7 | 8.0 | 15.8 | 8.3 | 9.2 | Wang et al., 2004a |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam | 4 | Day 9 | 2.7 | 4.7 | 2.1 | 1.9 | Wang et al., 2004a |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam | 4 | Day 11 | 1.2 | 2.4 | 1.3 | 1.2 | Wang et al., 2004a |
| Clarithromycinc | 500 | b.i.d. for 7 days | Midazolam | 4 | Day 14 | 0.9 | 1.6 | 1.1 | 1.0 | Wang et al., 2004a |
| Clarithromycinb | 500 | b.i.d. for 7 days | Midazolam | 8 | Day 7 | 8.4 | 16.2 | 8.9 | 9.2 | Gurley et al., 2006 |
| Clarithromycinb | 500 | b.i.d. for 7 days | Midazolam | 8 | Day 7 | 5.5 | 16.1 | 9.2 | 9.2 | Gurley et al., 2008 |
| Clarithromycinb | 500 | Single dose | Sildenafil | 50 | 2 h after | 2.3 | 4.3 | 3.4 | 9.3 | Hedaya et al., 2006 |
| Clarithromycinb | 500 | 4 doses for 2 days | Zolpidem | 5 | Day 2, 3rd dose | 1.0 | 1.8 | 1.7 | 1.9 | Farkas et al., 2009 |
| Clarithromycinb,d | 500 | b.i.d. for 9 days | Simvastatin | 40 | Day 8 | 10.0 | 31.3 | 21.2 | 7.9 | Jacobson, 2004 |
| Diltiazem IRb | 30 | t.i.d. for 3 days, 10 doses | Nifedipine | 20 | Day 4, 10th dose | 2.2 | 3.2 | 2.0 | 2.8 | Tateishi et al., 1989 |
| Diltiazem IRb | 90 | t.i.d. for 3 days, 10 doses | Nifedipine | 20 | Day 4, 10th dose | 3.1 | 8.0 | 3.6 | 4.6 | Tateishi et al., 1989 |
| Diltiazem IRb | 60 | 1 dose | Nifedipine | 20 | Day 1 | 1.3 | 1.4 | 1.4 | 2.3 | Ohashi et al., 1993 |
| Diltiazem IRb | 60 | t.i.d. for 3 days, 10 doses | Nifedipine | 20 | Day 4, 10th dose | 2.4 | 6.3 | 3.1 | 2.9 | Ohashi et al., 1993 |
| Diltiazem IRb | 60 | t.i.d. for 6 days, 19 doses | Nifedipine | 20 | Day 7, 19th dose | 3.0 | 6.3 | 3.0 | 2.9 | Ohashi et al., 1993 |
| Diltiazem IRb | 60 | t.i.d. for 2 days | Triazolam | 0.25 | D2, 5th dose | 3.4 | 3.9 | 2.5 | 3.0 | Varhe et al., 1996 |
| Diltiazem IRb | 60 | t.i.d. for 3 days, 10 doses | Triazolam | 0.25 | Day 4, 10th dose | 2.3 | 3.9 | 2.1 | 3.0 | Kosuge et al., 1997 |
| Diltiazem IRb | 60 | t.i.d. for 2 days, 5 doses | Midazolam | 15 | Day 2, 4th dose | 3.8 | 3.5 | 2.6 | 3.9 | Backman et al., 1994 |
| Diltiazem SRe | 120 | b.i.d. for 14 days, 28 doses | Simvastatin | 20 | Day14,27th dose | 4.8 | 20 | 11.6 | 4.9 | Mousa et al., 2000 |
| Diltiazem SRe | 120 | b.i.d. for 6 days, 6 doses | Midazolam | 4 | Day 6 | 4.0 | 10.5 | 5.1 | 5.7 | Zhang et al., 2009 |
| Diltiazem SRe | 120 | b.i.d. for 6 days, 6 doses | Midazolam i.v. | 0.05 | Day 6 | 1.7 | 4.0 | 2.2 | 3.3 | Zhang et al., 2009 |
| Diltiazem SRb,d | 240 | q.d. for 2 days | Midazolam | 2 | Day 2 | 3.3 | 4.9 | 3.4 | 5.2 | f |
| Diltiazem SRb,d | 240 | q.d. for 5 days | Midazolam | 2 | Day 5 | 3.3 | 5.9 | 3.3 | 5.2 | f |
| Erythromycinc,d | 500 | b.i.d. for 5 days | Sildenafil | 100 | Day 5 | 2.8 | 4.0 | 2.6 | 3.2 | Muirhead et al., 2002 |
| Erythromycinc | 400 | t.i.d. for 10 days | Alprazolam | 0.8 | Day 8 | 2.5 | 3.6 | 2.2 | 2.1 | Yasui et al., 1996 |
| Erythromycinb | 500 | 4 doses for 2 days | Triazolam | 0.125 | Day 2, 3rd dose | 3.7 | 2.4 | 1.9 | 2.3 | Greenblatt et al., 1998 |
| Erythromycinb | 200 | q.i.d. for 2 days | Midazolam | 5 | Day 2, 5th dose | 2.3 | 2.2 | 1.9 | 2.3 | Okudaira et al., 2007 |
| Erythromycinb | 200 | q.i.d. for 4 days | Midazolam | 5 | Day 4, 13th dose | 3.4 | 4.2 | 2.5 | 2.3 | Okudaira et al., 2007 |
| Erythromycinb | 200 | q.i.d. for 7 days | Midazolam | 5 | Day 7, 19th dose | 3.4 | 5.6 | 2.6 | 2.3 | Okudaira et al., 2007 |
| Erythromycinb | 500 | t.i.d. for 6 days | Midazolam | 15 | Day 6 | 4.4 | 8.2 | 3.9 | 3.3 | Olkkola et al., 1993 |
| Erythromycinb | 500 | t.i.d. for 6 days | Midazolam i.v. | 0.05 | Day 6 | 2.2 | 1.6 | 0.9 | 2.0 | Olkkola et al., 1993 |
| Erythromycinb | 500 | t.i.d. for 5 days | Midazolam | 15 | Day 5, 13th dose | 3.8 | 9.0 | 4.0 | 3.3 | Yeates et al., 1996 |
| Erythromycinb | 500 | t.i.d. for 2 days | Simvastatin | 40 | Day 2, 4th dose | 6.2 | 7.8 | 5.9 | 3.3 | Kantola et al., 1998 |
| Ritonavirb,d | 300–500 | t.i.d. for 7 days | Sildenafil | 100 | Day 7 | 11.0 | 2.8 | 10.5 | 17.8 | Muirhead et al., 2000 |
| Ritonavirb | 200 | 4 doses for 2 days | Alprazolam | 1 | Day 2, 2nd dose | 2.5 | 1.8 | 7.0 | 9.9 | Greenblatt et al., 2000a |
| Ritonavirb | 200 | 4 doses for 2 days | Triazolam | 0.125 | Day 2, 3rd dose | 20.4 | 3.0 | 19.8 | 13.0 | Greenblatt et al., 2000b |
| Ritonavirb | 200 | 4 doses for 2 days | Zolpidem | 5 | Day 2, 3rd dose | 1.3 | 2.0 | 2.1 | 2.0 | Greenblatt et al., 2000b |
| Saquinavirc,d | 1200 | t.i.d. for 7 days | Sildenafil | 100 | Day 7 | 3.1 | 1.0 | 6.3 | 11.7 | Muirhead et al., 2000 |
| Saquinavirb | 1200 | t.i.d. for 4 days | Midazolam | 7.5 | Day 3, 2nd dose | 5.1 | 1.0 | 7.6 | 10.9 | Palkama et al., 1999 |
| Saquinavirb | 1200 | t.i.d. for 4 days | Midazolam i.v. | 0.05 | Day 3, 2nd dose | 2.5 | 0.8 | 2.7 | 6.2 | Palkama et al., 1999 |
| Verapamil IRb | 2 × 40 | t.i.d. for 2 days, 5 doses | Midazolam | 15 | Day 2, 4th dose | 2.9 | 4.5 | 3.1 | 3.6 | Backman et al., 1994 |
| Verapamil IRb | 80 | t.i.d. for 2 days | Simvastatin | 40 | Day 2, 4th dose | 4.6 | 14.2 | 11.1 | 2.9 | Kantola et al., 1998 |
| Verapamil SRd | 480 | q.d. for 3 days | Simvastatin | 40 | Day 4 | 4.0 | 5.6 | 3.3 | 5.7 | Jacobson, 2004 |
| Verapamil SRb | 240 | q.d. for 8 days | Midazolam | 2 | Day 8 | 4.1 | 8.3 | 4.4 | 4.4 | Wang et al., 2005 |
| Verapamil SRb | 240 | q.d. for 8 days | Midazolam i.v. | 0.05 | Day 8 | 2.0 | 3.4 | 2.1 | 2.5 | Wang et al., 2005 |
| Fluoxetineb | 60 mg | q.d. 5 days, 20 mg for 7 days | Midazolam | 10 | Day 12 | 0.9 | 1.0 | 1.7 | 3.2 | Lam et al., 2003 |
| Fluoxetineb | 20 | q12 h for 6 days | Alprazolam | 1 | Day 3, 4th dose | 1.3 | 1.0 | 1.3 | 1.7 | Greenblatt et al., 1992 |
| Fluoxetinec | 60 | q.d. for 8 days | Triazolam | 0.25 | Day 8 | 1.0 | 1.0 | 2.1 | 3.1 | Wright et al., 1992 |
| Fluoxetineb | 20 | q.d. for 28 days, AM | Zolpidem | 10 | Day 28, PM | 1.0 | 1.0 | 1.0 | 1.4 | Allard et al., 1998 |
| Fluoxetineb | 20 | q.d. for 17 days, AM | Zolpidem | 10 | Day 17, PM | 1.0 | 1.0 | 1.1 | 1.4 | Piergies 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.