Predictions of CYP3A-mediated DDIs from in vitro inhibition parameters using the single incubation time method and the mechanistic method (52 clinical DDIs/13 drugs)

InhibitorInhibitor Dose Regimena[I]bfu, pVictim DrugcPredicted in AUC Single Incubation TimedFold Increase, Mechanistic MethodeObserved Fold Increase in AUCfReference
μM
Ketoconazole400 mg, q.d., 4 days, p.o.2.820.01Midazolam D4, 1 h after7.527.5915.90 ± 2.90Olkkola et al., 1994
Ketoconazole400 mg, q.d., 10 days, p.o.2.820.01Midazolam D67.507.599.51Chung et al., 2006
Ketoconazole200 mg, b.i.d., 2 days, p.o.3.460.01Midazolam D1, second8.478.5316.00 ± 6.1Tsunoda et al., 1999
Ketoconazole200 mg, b.i.d., 2 days, p.o3.460.01Midazolam, i.v., D1, second3.213.325.10 ± 1.90Tsunoda et al., 1999
Ketoconazole200 mg, b.i.d., 2 days, p.o.4.760.01Midazolam D210.0710.166.47 ± 3.4Eap et al., 2004
Ketoconazole200 mg, q.d., 12 days, p.o.1.880.01Midazolam D12, 1 h after5.956.007.72 ± 5.96Lam et al., 2003
Ketoconazole200 mg, s.d., p.o.1.870.01Midazolam 2 h after5.935.996.45McCrea et al., 1999
Fluconazole400 mg, s.d., p.o.21.550.89Midazolam 2 h after8.257.993.51 ± 1.7Olkkola et al., 1996
FluconazoleD1: 400 mg; D2–D5: 200 mg, q.d., p.o.29.990.89Midazolam D6, 2 h after9.759.463.60 ± 2.1Olkkola et al., 1996
Fluconazole100 mg, s.d., p.o.5.60.89Midazolam 1 h after3.713.602.16 ± 1.2Kharasch et al., 2005
Aprepitant125 mg, s.d., p.o.1.720.05Midazolam 1 h after1.961.862.27Majumdar et al., 2003
AprepitantD1: 125 mg; D2–D5: 80 mg, q.d., p.o.2.220.05Midazolam D5, 1 h after2.021.903.30Majumdar et al., 2003
Aprepitant40 mg, s.d., p.o.0.410.05Midazolam 1 h after1.721.671.22Majumdar et al., 2003
AprepitantD1: 40 mg; D2–D5: 25 mg, q.d., p.o.0.30.05Midazolam D5, 1 h after1.711.701.02Majumdar et al., 2003
Aprepitant125 mg, s.d., p.o.3.110.05Midazolam, i.v., 1 h after1.141.151.47 ± 0.14Majumdar et al., 2007
VoriconazoleD1: 400 mg; D2: 200 mg, b.i.d., p.o.1.640.42Midazolam, i.v., D2, 1 h after1.571.533.61Saari et al., 2006
VoriconazoleD1: 400 mg; D2: 200 mg, b.i.d., p.o.1.460.42Midazolam D2, 1 h after3.233.169.85Saari et al., 2006
NefazodoneD1–D4: 100 mg titration to 200 mg, b.i.d.; D5–D12: 200 mg, b.i.d., p.o.1.730.01Midazolam D12, 1 h after second4.6611.664.44Lam et al., 2003
Troleandomycin500 mg, b.i.d., p.o.1.760.04Midazolam, i.v., 2 h after first5.837.203.02 ± 1.44Phimmasone and Kharasch, 2001
Troleandomycin500 mg, b.i.d., p.o.1.760.04Midazolam, i.v., 2 h after first5.837.204.50 ± 1.0Kharasch et al., 2004
Troleandomycin500 mg, b.i.d., p.o.1.760.04Midazolam, 2 h after first15.8819.7915.70 ± 2.17Kharasch et al., 2004
Erythromycin200 mg, q.i.d., 7 days, p.o.0.440.16Midazolam D7, 1 h after first2.376.873.38 ± 1.40Okudaira et al., 2007
Erythromycin200 mg, q.i.d., 4 days, p.o.0.440.16Midazolam D4, 1 h after first2.376.873.38 ± 1.60Okudaira et al., 2007
Erythromycin200 mg, q.i.d., 2 days, p.o.0.440.16Midazolam D2, 1 h after first2.376.872.32 ± 0.90Okudaira et al., 2007
Erythromycin500 mg, t.i.d., 5 days, p.o.0.950.16Midazolam D5, 1.5 h after first3.0810.463.81 ± 0.70Zimmermann et al., 1996
Erythromycin500 mg, t.i.d., 6 days, p.o.4.220.16Midazolam D6, 2 h after second6.4718.054.41 ± 1.04Olkkola et al., 1993
Erythromycin500 mg, t.i.d., 6 days, p.o.1.640.16Midazolam, i.v., D6, 2 h after second1.645.112.17 ± 0.38Olkkola et al. 1993
Clarithromycin500 mg, b.i.d., 7 days, p.o.0.900.5Midazolam, i.v., D7, 2 h after first1.503.513.10 ± 0.70Gorski et al., 1998
Clarithromycin500 mg, b.i.d., 7 days, p.o.3.200.5Midazolam, i.v., D7, 2 h after first2.475.843.20 ± 0.60Quinney et al., 2008b
Clarithromycin250 mg, b.i.d., 5 days, p.o.2.40.5Midazolam D5, 1.5 h after first5.2414.113.60Yeates et al., 1996
Clarithromycin500 mg, b.i.d., 7 days, p.o.0.900.5Midazolam D7, 2 h after first3.198.898.10 ± 2.40Gorski et al., 1998
Clarithromycin500 mg, b.i.d., 7 days, p.o.3.200.5Midazolam D7, 2 h after first6.1815.648.00 ± 2.20Quinney et al., 2008b
Clarithromycin500 mg, b.i.d., 7 days, p.o.0.900.5Midazolam D7, 2 h after first3.198.895.75 ± 0.62Gurley et al., 2008
Clarithromycin500 mg, b.i.d., 7 days, p.o.0.900.5Midazolam D7, 2 h after first3.198.897.79 ± 1.79Gurley et al., 2006
DiltiazemD1: 60 mg, b.i.d.; D2: 60 mg, t.i.d., p.o.0.380.22Midazolam D2, 1 h after second2.3613.693.75 ± 0.11Backman et al., 1994
Diltiazem120 mg, b.i.d., 6 days, p.o.0.160.22Midazolam, i.v., D61.093.601.77 ± 0.21Zhang et al., 2009
Diltiazem120 mg, b.i.d., 6 days, p.o.0.160.22Midazolam D62.019.304.11 ± 0.46Zhang et al., 2009
Saquinavir1200 mg, t.i.d., 5 days, p.o.0.590.02Midazolam, i.v., D3, 2 h after second1.144.372.49Palkama et al., 1999
Saquinavir1200 mg, t.i.d., 5 days, p.o.0.590.02Midazolam D3, 2 h after second2.2511.485.14Palkama et al., 1999
Saquinavir1200 mg, t.i.d., 7 days, p.o.1.150.02Sildenafil D73.7510.243.10Muirhead et al., 2000
Itraconazole200 mg, q.d., 4 days, p.o.0.280.002Midazolam D4, 1 h after5.2810.1210.79 ± 0.12Olkkola et al., 1994
Itraconazole200 mg, q.d., 6 days, p.o.0.480.002Midazolam D6, 2 h after7.2112.946.60Olkkola et al., 1996
Itraconazole200 mg, q.d., 6 days, p.o.0.110.002Midazolam D1, 2 h after3.286.073.4Olkkola et al., 1996
Itraconazole200 mg, q.d., 4 days, p.o.0.110.002Midazolam D43.276.076.75Backman et al., 1998
Itraconazole100 mg, q.d., 4 days, p.o.0.190.002Midazolam D4, 2 h after4.278.255.74 ± 0.15Ahonen et al., 1995
μM
Conivaptan40 mg, s.d., p.o.1.570.01Midazolam3.9116.553.00NDA 021697
Conivaptan40 mg, s.d., p.o.1.570.01Midazolam, i.v.1.916.422.00NDA 021697
Ritonavir500 mg, b.i.d.,7 days, p.o.14.090.02Sildenafil D712.2712.4611Muirhead et al., 2000
RitonavirD1: 200 mg, t.i.d.; D2: 300 mg, t.i.d.; D3: 300 mg, q.d., p.o.11.090.02Fentanyl, i.v., D2, 2 h after second1.361.362.7Olkkola et al., 1999
Ritonavir200 mg, b.i.d., 2 days, p.o.1.660.02Triazolam D2, 1 h after first9.6011.1220.60 ± 1.09Greenblatt et al., 2000b
RitonavirD1: 200 mg, q.d.; D2: 200 mg, b.i.d.; D3: 200 mg, q.d., p.o.2.210.02Alprazolam D2, 1 h after first4.995.572.47 ± 0.06Greenblatt et al., 2000a
Ritonavir200 mg, q.d., 2d, p.o.3.240.02Trazodone D2, 1 h after first2.022.052.34 ± 0.17Greenblatt et al., 2003
  • Inhibitor dose regimen: e.g., 400 mg, q.d., 10 days, p.o. represents the inhibitor dosed at 400 mg, once a day for 10 consecutive days.

  • The source of [I] is listed in detail in the supplement data.

  • Victim drug: e.g., midazolam D12, 1 h after second represents at the 12th day, midazolam was given orally 1 h after the second dose of the inhibitor.

  • Single incubation time: using the single IC50 value (20-min inhibitor incubation alone, the value listed in the first column in Table 1) with a model based on the reversible inhibition mechanism (eqs. 5 and 7).

  • Mechanistic method: using the inhibition parameters estimated from models A to C (values listed in Table 2) with the corresponding model for a given mechanism of inhibition (eqs. 5, 711).

  • Clinically observed DDIs calculated by AUC in the presence and absence of inhibitor (mean ± S.D.).