TABLE 5

Comparisons of the predicted DDIs from the in vitro CYP3A4 induction in hepatocytes of the two liver donors (PRED1 and PRED2) with the clinical observed DDIs reported in cited references


Inducer

Dose Regimena

Substrate

Dose Regimenb

AUC Ratioc

References
PRED1
PRED2
OBSd
BST 125 mg b.i.d. 7 days Ethinyl estradiol 35 μg SD 0.87 0.94 0.69 van Giersbergen et al., 2006
BST 125 mg b.i.d. 4.5 days Glyburide 2.5 mg b.i.d. 9.5 days 0.84 0.92 0.6 van Giersbergen et al., 2002
BST 62.5 mg b.i.d. 4 wk Sildenafil 100 mg SD 0.66 0.81 0.47 Paul et al., 2005
BST 62.5 mg b.i.d. 8 wk Sildenafil 100 mg SD 0.66 0.81 0.31 Paul et al., 2005
BST 125 mg b.i.d. 5.5 days Simvastatin 40 mg q.d. 5.5 days 0.59 0.75 0.66 Dingemanse et al., 2003
DEX 10 mg q.d. 2 days Cyclophosphamide 350-420 mg infusion 2 days 1.00 1.00 0.57 Moore et al., 1988
DEX 1.5 mg q.d. 4 days Triazolam 0.5 mg SD 0.87 0.69 0.81 Villikka et al., 1998
EFA 600 mg, q.d. 7 days Amprenavir 1200 mg b.i.d. 0.71 0.69 0.76 Falloon et al., 2000
EFA 600 mg, q.d. 2 wk Amprenavir 600 mg b.i.d. 5.8 mo 0.71 0.69 0.6 Goujard et al., 2003
EFA 600 mg q.d. 20 days Amprenavir 600 mg b.i.d. 10 days 0.63 0.67 0.43 Morse et al., 2005
EFA 600 mg q.d. 15 days Atorvastatin 10 mg SD 0.63 0.61 0.59 Gerber et al., 2005
EFA 600 mg q.d. 14 days Indinavir 800 mg b.i.d. 30 days 0.56 0.46 0.75 Aarnoutse et al., 2002
EFA 600 mg q.d. 4 wk Indinavir 800 mg b.i.d. 4 wk 0.56 0.46 0.93 Boyd et al., 2003a
EFA 600 mg q.d. 14-21 days Methadone 35-100 mg daily (maintenance therapy) 0.60 0.64 0.43 Clarke et al., 2001
EFA 600 mg q.d. 15 days Pravastatin 40 mg SD 0.51 0.49 0.44 Gerber et al., 2005
EFA 600 mg q.d. 10 days Ritonavir 200 mg q.d. 20 days 0.79 0.72 0.8 la Porte et al., 2004b
EFA 600 mg q.d. 14 days Ritonavir 200 mg q.d. 28 days 0.79 0.72 0.78 Wire et al., 2004
EFA 600 mg q.d. 14 days Ritonavir 100 mg b.i.d. 30 days 0.70 0.68 0.64 Aarnoutse et al., 2002
EFA 600 mg q.d. 2 wk Ritonavir 100 mg b.i.d. 5.8 mo 0.70 0.68 0.45 Goujard et al., 2003
EFA 600 mg q.d. 14 days Amprenavir 1395 mg q.d. 28 days 0.80 0.72 0.87 Wire et al., 2004
EFA 600 mg q.d. 14 days Amprenavir 700 mg b.i.d. 28 days 0.80 0.72 0.93 Wire et al., 2004
EFA 600 mg q.d. 14 days Amprenavir 700 mg b.i.d. 28 days 0.80 0.72 0.91 Wire et al., 2004
EFA 600 mg q.d. 4 wk Ritonavir 100 mg b.i.d. 4 wk 0.79 0.72 0.98 Boyd et al., 2003a
EFA 600 mg q.d. 14 days Ritonavir 100 mg b.i.d. 28 days 0.79 0.72 0.76 Wire et al., 2004
EFA 600 mg q.d. 35 days Ritonavir 100 mg b.i.d. 35 days 0.79 0.72 0.95 Hsu et al., 2003
PB 100 mg q.d. 14 days Antipyrine 1 g SD 0.53 0.72 0.79 Leclercq et al., 1989
PB 100 mg q.d. 8 days Antipyrine 250 mg SD 0.53 0.72 0.66 Schellens et al., 1989
PB 100 mg q.d. 8 days Nifedipine 20 mg SD 0.31 0.50 0.39 Schellens et al., 1989
PB 50-90 mM (SS) Quinidine 300 mg SD 0.32 0.51 0.34 Data et al., 1976
PB 100 mg q.d. 8 days Tirilazadc 105 mg i.v. QID 7 days 0.41 0.61 0.8 Fleishaker et al., 1996
PB 100 mg q.d. 8 days Tirilazadc 105 mg i.v. q.i.d. 7 days 0.41 0.61 0.76 Fleishaker et al., 1996
PB 100 mg q.d. 21 days Verapamil 1.05 mg SD 0.42 0.62 0.66 Rutledge et al., 1988
PB 100 mg q.d. 21 days Verapamil 80 mg SD 0.40 0.59 0.23 Rutledge et al., 1988
PB 100 mg q.d. 21 days Verapamil 80 mg q.i.d. 5 days 0.40 0.59 0.21 Rutledge et al., 1988
RIF 100 mg q.d. 14 days Antipyrine 1 g SD 0.53 0.72 0.84 Leclercq et al., 1989
RIF 100 mg q.d. 16 days Losartan 50 mg q.d. 7 days 0.65 0.83 0.97 Goldberg et al., 1996
RIF 600 mg q.d. 12 days (R)-Verapamil 10 mg SD 0.20 0.18 0.5 Fromm et al., 1996
RIF 600 mg q.d. 12 days (R)-Verapamil 120 mg b.i.d. 24 days 0.20 0.18 0.02 Fromm et al., 1996
RIF 600 mg q.d. 12 days (R)-Verapamil 120 mg b.i.d. 16 days 0.20 0.18 0.01 Fromm et al., 1998
RIF 600 mg q.d. 12 days (S)-Verapamil 120 mg b.i.d. 16 days 0.20 0.18 0.03 Fromm et al., 1998
RIF 600 mg q.d. 12 days (S)-Verapamil 120 mg b.i.d. 24 days 0.20 0.18 0.03 Fromm et al., 1996
RIF 600 mg q.d. 5 days Alfentanil 1.125 mg SD 0.10 0.09 0.43 Phimmasone and Kharasch, 2001
RIF 600 mg q.d. 5 days Alfentanil 1.125 mg SD 0.10 0.09 0.38 Kharasch et al., 2004b
RIF 600 mg q.d. 5 days Alfentanil 4.5 mg SD 0.10 0.09 0.05 Kharasch et al., 2004b
RIF 450 mg q.d. 4 days Alprazolam 1 mg SD 0.12 0.11 0.12 Schmider et al., 1999
RIF 600 mg q.d. 18 days Amprenavir 1200 mg b.i.d. 8 days 0.30 0.27 0.18 Polk et al., 2001
RIF 300 mg b.i.d. 8 days Antipyrine 1000 mg SD 0.29 0.28 0.61 Leclercq et al., 1989
RIF 300 mg b.i.d. 8 days Antipyrine 1000 mg SD 0.29 0.28 0.53 Leclercq et al., 1989
RIF 600 mg q.d. 15 days Antipyrine 1200 mg SD 0.28 0.26 0.41 Bennett et al., 1982
RIF 600 mg q.d. 5 days Atorvastatin 40 mg SD 0.23 0.21 0.2 Backman et al., 2005
RIF 600 mg q.d. 7 days Budesonide 3 mg SD 0.11 0.10 0.01 Dilger et al., 2005
RIF 600 mg q.d. 7 days Budesonide 3 mg SD 0.11 0.10 0.003 Dilger et al., 2005
RIF 600 mg q.d. 5 days Buspirone 30 mg SD 0.09 0.08 0.09 Kivistö et al., 1999
RIF 600 mg q.d. 5 days Buspirone 30 mg SD 0.09 0.08 0.08 Lamberg et al., 1998
RIF 600 mg q.d. 11 days Cyclosporine 750 mg SD 0.11 0.10 0.27 Hebert et al., 1992
RIF 600 mg b.i.d. 7 days Diazepam 10 mg SD 0.29 0.26 0.27 Ohnhaus et al., 1987
RIF 300 mg b.i.d. 7 days Diazepam 10 mg SD 0.29 0.27 0.24 Ohnhaus et al., 1987
RIF 300 mg b.i.d. 10 days Ethinyl estradiol 35 μg q.d. (2 cycles) 0.34 0.31 0.36 LeBel et al., 1998
RIF 600 mg q.d. 14 days Ethinyl estradiol 35 μg (chronic treatment) q.d. 0.34 0.31 0.34 Barditch-Crovo et al., 1999
RIF 600 mg q.d. 13 days Everolimus 4 mg SD 0.11 0.10 0.38 Kovarik et al., 2002
RIF 600 mg q.d. 16 days Gefitinib 500 mg SD 0.18 0.16 0.17 Swaisland et al., 2005
RIF 600 mg q.d. 5 days Glyburide 1.75 mg SD 0.28 0.26 0.61 Niemi et al., 2001
RIF 600 mg q.d. 11 days Imatinib 400 mg SD 0.25 0.23 0.26 Bolton et al., 2004
RIF 450 mg q.d. 6 wk Irinotecan 75 mg/m2 q.d. (4 cycles) 0.77 0.77 0.94 Yonemori et al., 2004
RIF 300 mg b.i.d. 7 days Losartan 50 mg q.d. 7 days 0.33 0.32 0.65 Williamson et al., 1998
RIF 600 mg q.d. 10 days Methadone 5.5 mg SD 0.28 0.25 0.32 Kharasch et al., 2004a
RIF 600 mg q.d. 10 days Methadone 11.2 mg SD 0.28 0.25 0.23 Kharasch et al., 2004a
RIF 600 mg q.d. 14 days Midazolam 2 mg SD 0.10 0.09 0.14 Adams et al., 2005
RIF 600 mg q.d. 9 days Midazolam 5.5 mg SD 0.10 0.09 0.12 Chung et al., 2006
RIF
600 mg q.d. 7 days
Midazolam
6 mg SD
0.10
0.09
0.1
Gorski et al., 2003
RIF 300 mg b.i.d. 7 days Midazolam 8 mg SD 0.10 0.09 0.06 Gurley et al., 2006
RIF 600 mg q.d. 5 days Midazolam 3 mg SD 0.10 0.09 0.05 Kharasch et al., 2004b
RIF 450 mg q.d. 5 days Midazolam 7.5 mg SD 0.10 0.09 0.05 Eap et al., 2004
RIF 600 mg q.d. 5 days Midazolam 15 mg SD 0.10 0.09 0.04 Backman et al., 1996
RIF 600 mg q.d. 5 days Midazolam 15 mg SD 0.10 0.09 0.02 Backman et al., 1998
RIF 450 mg q.d. 4 days Nifedipine 20 mg q.i.d. (stable therapy) 0.14 0.14 0.54 Tsuchihashi et al., 1987
RIF 450 mg, q.d. >30 days Nifedipine 20 mg b.i.d. (stable therapy) 0.14 0.14 0.39 Tada et al., 1992
RIF 600 mg q.d. 7 days Nifedipine 20 mg SD 0.13 0.12 0.08 Holtbecker et al., 1996
RIF 600 mg q.d. 6 wk Prednisolone 10 mg i.v. 0.27 0.24 0.67 Powell-Jackson et al., 1983
RIF 300-450 mg q.d. 3 wk Prednisolone 20 mg infusion 0.28 0.27 0.53 Bergrem and Refvem, 1983
RIF 600 mg q.d. 7 days Quinidine 450 mg SD 0.14 0.12 0.27 Twum-Barima and Carruthers, 1981
RIF 600 mg q.d. 7 days Quinidine 450 SD 0.14 0.12 0.17 Twum-Barima and Carruthers, 1981
RIF 600 mg q.d. 2 wk Quinine 600 mg SD 0.17 0.16 0.17 Wanwimolruk et al., 1995
RIF 600 mg q.d. 7 days Repaglinide 4 mg SD 0.24 0.22 0.52 Bidstrup et al., 2004
RIF 600 mg q.d. 5 days Repaglinide 37.5 mg SD 0.24 0.22 0.43 Niemi et al., 2000
RIF 600 mg q.d. 7 days Repaglinide 4 mg SD 0.24 0.22 0.2 Bidstrup et al., 2004
RIF 600 mg q.d. 5 days Ropivacainec 45 mg SD 0.68 0.65 0.62 Jokinen et al., 2001b
RIF 600 mg q.d. 5 days Ropivacainec 45 mg SD 0.68 0.65 0.48 Jokinen et al., 2001b
RIF 600 mg q.d. 14 days Saquinavir 1200 mg t.i.d. 14 days 0.21 0.19 0.3 Grub et al., 2001
RIF 600 mg q.d. 5 days Simvastatin 40 mg SD 0.10 0.09 0.14 Kyrklund et al., 2000
RIF 600 mg q.d. 9 days Simvastatin 40 mg SD 0.10 0.08 0.09 Chung et al., 2006
RIF 600 mg, q.d. >31 days Tacrolimus 15 mg SD 0.25 0.23 0.45 Kuypers et al., 2005
RIF 600 mg q.d. 18 days Tacrolimus 75 mg SD 0.25 0.23 0.32 Hebert et al., 1999
RIF 600 mg q.d. 5 days Triazolam 0.5 mg SD 0.10 0.09 0.05 Villikka et al., 1997a
RIF 600 mg q.d. 15 days Verapamil 120 mg SD 0.20 0.18 0.07 Barbarash et al., 1988
RIF 600 mg q.d. 5 days Zolpidem 20 mg SD 0.27 0.25 0.28 Villikka et al., 1997b
CMZ 600 mg q.d. 21 days Ethinyl estradiol 35 μg q.d. 21 days 0.67 0.71 0.58 Doose et al., 2003
CMZ 300-600 mg q.d. 8-12 wk Ethinyl estradiol 50 μg SD 0.67 0.71 0.58 Crawford et al., 1990
CMZ 200 mg q.d. 6 days Etizolam 1 mg SD 0.55 0.68 0.54 Kondo et al., 2005
CMZ 400 mg q.d. 28 days Mirtazapine 30 mg SD 7 days 0.40 0.20 0.39 Sitsen et al., 2001
CMZ 400 mg q.d. 21 days Mirtazapine 30 mg SD 28 days 0.40 0.20 0.37 Sitsen et al., 2001
CMZ 400-600 mg b.i.d. 3 wk Omeprazole 20 mg SD 0.50 0.52 0.6 Laroudie et al., 2000
CMZ 600-1750 mg 2-12 mo Prednisolone 35 mg i.v. SD 0.49 0.30 0.67 Olivesi, 1986
CMZ
300 mg b.i.d. 14 days
Simvastatin
80 mg SD
0.30
0.34
0.26
Ucar et al., 2004
  • SD, single dose used for the substrate drug.

  • a Dose regimens of the inducers, e.g., 125 mg b.i.d. 7 days represents a dose (125 mg) that was given orally twice a day for 7 days.

  • b Dose regimens of the CYP3A4 substrate drugs.

  • c AUC ratios of the drugs in the presence and absence of the inducers predicted from the in vitro induction data in hepatocytes of donor 1 (PRED 1) and donor 2 (PRED 2), respectively.

  • d Observed in vivo DDIs from the corresponding references.