TABLE 1

Summary of the 48 in vivo clinical studies used in prediction

Precipitant
Precipitant Dose
Precipitant Dose Interval
Dose Type
[I] = Csys
fu
Midazolam Dose
Dose Type
Observed DDIa
Referencesb
Atomoxetine 60 mg (12 days) b.i.d. p.o. 10.6 0.020 5 mg p.o. 1.2 Sauer et al., 2004
Atorvastatin 10-40 mg (10 days) q.d. p.o. 0.023 0.020 0.15 mg/kg i.v. 1.41 Mc Donnell et al., 2003
Azithromycin 500 mg (3 days) q.d. p.o. 0.270 0.120 15 mg p.o. 1.27 Zimmermann et al., 1996
Carbamazepine 600-800 mg b.i.d. p.o. 34 0.26 15 mg p.o. 0.04 Backman et al., 1996
Chlorzoxazone 250 mg q.d. p.o. 23.6 0.019 5 mg p.o. 1.68 Palmer et al., 2001
Cimetidine 400 mg Single dose p.o. 3.27 0.790 15 mg p.o. 1.37 Fee et al., 1987
Cimetidine 400 mg (1.5 days) b.i.d. p.o. 9.92 0.790 15 mg p.o. 1.35 Salonen et al., 1986
Cimetidine 800 mg Single dose p.o. 9.92 0.790 7.5 mg p.o. 1.50 Martinez et al., 1999
Cimetidine 200 mg + 400 mg (1.5 days) q.i.d. p.o. 3.27 0.790 15 mg p.o. 2.02 Elliott et al., 1984
Clarithromycin 250 mg (5 days) b.i.d. p.o. 2.40 0.300 15 mg p.o. 3.57 Yeates et al., 1996
Clarithromycin 500 mg (7 days) b.i.d. p.o. 3.00 0.300 8 mg p.o. 8.40 Gurley et al., 2006
Conivaptan 20 mg (5 days) b.i.d. p.o. 0.159 0.015 2 mg p.o. 3.49 NDA 021697
Conivaptan 40 mg (5 days) b.i.d. p.o. 0.433 0.016 2 mg p.o. 5.76 NDA 021697
Diltiazem 60 mg (2 days) t.i.d. p.o. 0.140 0.220 15 mg p.o. 3.75 Backman et al., 1994b
Erythromycin 500 mg (5 days) t.i.d. p.o. 0.950 0.160 15 mg p.o. 3.81 Zimmermann et al. 1996
Erythromycin 500 mg (7 days) t.i.d. p.o. 0.950 0.160 15 mg p.o. 4.42 Olkkola et al., 1993
Fluconazole 400 mg Single dose p.o. 29.4 0.890 1 mg i.v. 1.94 Kharasch et al., 2005
Fluconazole 400 mg, 200 mg (5 days) q.d. p.o. 29.4 0.890 7.5 mg p.o. 3.60 Olkkola et al., 1996
Flumazenil 1.75 mg Single dose i.v. 0.001 0.600 0.35 mg i.v. 0.97 Rogers et al., 2002
Fluoxetine 60 mg (5 days), 20 mg (7 days) q.d. p.o. 0.353 0.050 10 mg p.o. 0.87 Lam et al., 2003
Fluvoxamine 50-100 mg (12 days) b.i.d. p.o. 0.342 0.230 10 mg p.o. 1.66 Lam et al., 2003
Gatifloxacin 400 mg (5 days) q.d. p.o. 3.82 0.800 1 mg i.v. 1.80 Grasela et al., 2000
Itraconazole 200 mg (4 days) q.d. p.o. 0.270 0.002 7.5 mg p.o. 10.8 Olkkola et al., 1994
Itraconazole 100 mg (4 days) q.d. p.o. 0.128 0.002 7.5 mg p.o. 5.74 Ahonen et al., 1995
Itraconazole 200 mg (6 days) q.d. p.o. 0.270 0.002 7.5 mg p.o. 6.64 Olkkola et al., 1996
Itraconazole 200 mg (4 days) q.d. p.o. 0.270 0.002 7.5 mg p.o. 6.16 Backman et al., 1998
Ketoconazole 200 mg (1.5 days) b.i.d. p.o. 5.42 0.010 2 mg i.v. 5.0 Tsunoda et al., 1999
Ketoconazole 200 mg (1.5 days) b.i.d. p.o. 5.42 0.010 6 mg p.o. 13.6 Tsunoda et al., 1999
Ketoconazole 200 mg (5 days) Single dose p.o. 1.87 0.010 2 mg p.o. 5.2 McCrea et al., 1999
Ketoconazole 200 mg (5 days) Single dose p.o. 1.87 0.010 2 mg p.o. 6.5 McCrea et al., 1999
Ketoconazole 200 mg (12 days) q.d. p.o. 1.88 0.010 10 mg p.o. 8.7 Lam et al., 2003
Ketoconazole 200 mg (4 days) b.i.d. p.o. 4.76 0.010 75 ug p.o. 6.5 Eap et al., 2004
Ketoconazole 400 mg (10 days) q.d. p.o. 2.82 0.010 5.5 mg p.o. 9.5 Chung et al., 2006
Ketoconazole 400 mg (4 days) q.d. p.o. 2.82 0.010 7.5 mg p.o. 15.9 Olkkola et al., 1994
Mibefradil 100 mg Single dose p.o. 1.24 0.005 2 mg p.o. 8.9 Veronese et al., 2003
Nefazodone 100-200 mg (12 days) b.i.d. p.o. 1.73 0.009 10 mg p.o. 5.4 Lam et al., 2003
Nitrendipine 20 mg (4 days) q.d. p.o. 0.041 0.016 20 mg i.v. 0.9 Handel et al., 1988
Parecoxib 40 mg Single dose i.v. 2.53 0.020 0.07 mg/kg i.v. 1.1 Ibrahim et al., 2002
Ranitidine 150 mg (1.5 days) b.i.d. p.o. 1.47 0.850 15 mg p.o. 1.2 Fee et al., 1987
Ranitidine 300 mg Single dose p.o. 1.47 0.850 7.5 mg p.o. 1.3 Martinez et al., 1999
Ranitidine 150 mg (1.5 days) b.i.d. p.o. 1.15 0.850 15 mg p.o. 1.7 Elliott et al., 1984
Rifampin 600 mg (5 days) q.d. p.o. 12.50 0.250 8 mg p.o. 0.1 Backman et al., 1996
Roxithromycin 300 mg (6 days) q.d. p.o. 5.13 0.140 15 mg p.o. 1.5 Backman et al., 1994a
Saquinavir 1200 mg (5 days) t.i.d. p.o. 0.430 0.020 7.5 mg p.o. 5.2 Palkama et al., 1999
Saquinavir 1200 mg (5 days) t.i.d. p.o. 0.430 0.020 0.05 mg/kg i.v. 2.5 Palkama et al., 1999
Simvastatin 80 mg (7 days) q.d. p.o. 0.026 0.060 2 mg p.o. 1.1 Prueksaritanont et al., 2000
Terbinafine 250 mg (4 days) q.d. p.o. 2.13 0.010 7.5 mg p.o. 0.76 Ahonen et al., 1995
Troleandomycin 500 mg (2 days) b.i.d. p.o. 1.76 0.038 10 mg p.o. 14.8 Kharasch et al., 2004
Valdecoxib 40 mg b.i.d. p.o. 2.90 0.020 10 mg p.o. 1.1 Unpublished data
Verapamil
80 mg (2 days)
t.i.d.
p.o.
0.480
0.100
15 mg
p.o.
2.9
Backman et al., 1994b

  • NDA, New Drug Application.

  • ↵ a Observed DDI = ratio of midazolam AUC in the presence and absence of precipitant.

  • ↵ b See supplemental data for additional reference information used for the in vivo data.