Supplemental fig.1 Predicted AUC ratios based on substrate – independent IRs
1
2
3
4
nifedipine – diltiazem
nifedipine – verapamil
cyclosporin – clarithromycin
cyclosporin – diltiazem
-1-
Supplemental table I Interaction studies used to determine the imprecision on AUC ratios.
All the data were taken from Guest EJ 2011 (1)
Alprazolam
Drug dose
(mg)
1
Ketoconazole
Inhibitor
dose
400 mg/d
Observed AUC
ratio
3.98
Alprazolam
1
Ketoconazole
400 mg/d
1.76
Alprazolam
0.8
Itraconazole
200 mg/d
2.66
Midazolam
7.5
Flucoconazole
200 mg/d
3.6
Midazolam
0.075
Ketoconazole
400 mg/d
6.47
Midazolam
10
Ketoconazole
200 mg/d
6.56
Midazolam
7.5
Ketoconazole
400 mg/d
15.9
Midazolam
6
Ketoconazole
400 mg/d
16
Midazolam
5.5
Ketoconazole
400 mg/d
9.51
Midazolam
2
Ketoconazole
200 mg sd
4.95
Midazolam
2
Ketoconazole
200 mg sd
6.45
Midazolam
7.5
Itraconazole
100 mg/d
5.75
Midazolam
7.5
Itraconazole
200 mg/d
6.16
Midazolam
7.5
Itraconazole
200 mg/d
10.8
Midazolam
7.5
Itraconazole
200 mg/d
6.64
Triazolam
0.25
Flucoconazole
100 mg/d
2.46
Triazolam
0.25
Flucoconazole
50 mg/d
1.63
Triazolam
0.25
Flucoconazole
100 mg/d
2.05
Triazolam
0.25
Flucoconazole
200 mg/d
4.42
Triazolam
0.25
Ketoconazole
400 mg/d
13.7
Triazolam
0.25
Ketoconazole
400 mg/d
9.17
Triazolam
0.125
Ketoconazole
400 mg/d
9.16
Triazolam
0.25
Itraconazole
200 mg/d
10.5
Drug
Inhibitor
sd: single dose
-2-
Supplemental table II
Data used to assess the hypothesis of substrate-independence of inhibiting power of the
inhibitors
CR3A4 = contribution ratio (i.e. fraction metabolized in vivo) of the substrate by CYP3A4
IR3A4 = inhibition ratio (i.e. inhibition power in vivo) of the inhibitor for CYP3A4
Inhibitor, dose (mg/d)
Substrate
Observed
AUC ratio
CR3A4
Substrate-
Substrate-
dependent
independent
IR3A4
IR3A4
Ref. for the
observed AUC ratio
Clarithromycin 1000
Midazolam
8.4
0.913
0.965
0.94
(2)
Diltiazem 60-120
Midazolam
3.8
0.913
0.807
0.714
(2)
Erythromycin 1500
Midazolam
4
0.913
0.821
0.805
(2)
Grapefruit RS¥
Midazolam
2
0.913
0.548
0.51
(3)
Grapefruit DS§
Midazolam
6
0.913
0.913
0.931
(3)
Fluconazole 200
Midazolam
3.6
0.913
0.791
0.748
(1)
Itraconazole 200
Midazolam
7.9
0.913
0.957
0.954
(1)
Ketoconazole 400
Midazolam
10.9
0.913
0.995
0.98
(1)
Verapamil 240
Midazolam
2.9
0.913
0.718
0.687
(2)
Clarithromycin 1000
Simvastatin
10
0.973
0.925
0.94
(2)
Diltiazem 90
Simvastatin
2
0.973
0.514
0.714
(4)
Erythromycin 1500
Simvastatin
6.2
0.973
0.862
0.805
(2)
Grapefruit RS¥
Simvastatin
3.6
0.973
0.742
0.51
(2)
Grapefruit DS§
Simvastatin
13.5
0.973
0.952
0.931
(2)
Itraconazole 200
Simvastatin
18.6
0.973
0.972
0.954
(5)
Ketoconazole 400
Simvastatin
12.4
0.973
0.945
0.98
(2)
Verapamil 240
Simvastatin
4.6
0.973
0.804
0.687
(2)
Diltiazem 60-120
Nifedipine
1.51
0.717
0.471
0.714
(6)
Grapefruit RS
Nifedipine
1.35
0.717
0.362
0.51
(7)
Verapamil 180 SR
Nifedipine
1.18
0.717
0.213
0.687
(8)
Grapefruit RS
Nisoldipine
1.76
0.972
0.444
0.51
(7)
Ketoconazole 400
Nisoldipine
24
0.972
0.986
0.98
(5)
Erythromycin 1500
Felodipine
2.5
0.866
0.693
0.805
(2)
Grapefruit RS¥
Felodipine
2
0.866
0.577
0.51
(7)
-3-
Itraconazole 200
Felodipine
6.3
0.866
0.971
0.954
(5)
Erythromycin 1500
Eplerenone
2.9
0.793
0.826
0.805
(9)
Fluconazole 200
Eplerenone
2.20
0.793
0.688
0.748
(9)
Ketoconazole 400
Eplerenone
5.41
0.793
1.028
0.98
(9)
Verapamil 240
Eplerenone
2
0.793
0.631
0.687
(9)
Clarithromycin 1000
Saquinavir
2.8
0.579
1.110
0.94
(9)
Erythromycin 1500
Saquinavir
1.8
0.579
0.768
0.805
(9)
Grapefruit RS¥
Saquinavir
1.5
0.579
0.576
0.51
(10)
Grapefruit DS§
Saquinavir
2.2
0.579
0.942
0.931
(10)
Fluconazole 200
Saquinavir
1.5
0.579
0.576
0.748
(9)
Itraconazole 100
Saquinavir
2.14
0.579
0.920
0.954
(11)
Ketoconazole 400
Saquinavir
2.9
0.579
1.132
0.98
(9)
Clarithromycin 1000
Cyclosporin
1.49
0.681
0.483
0.94
(12)
Diltiazem 60-120
Cyclosporin
1.4
0.681
0.420
0.714
(13)
Erythromycin 1500
Cyclosporin
2.35
0.681
0.844
0.805
(14)
Grapefruit RS¥
Cyclosporin
1.86
0.681
0.679
0.51
(15)
Fluconazole 200
Cyclosporin
2.22
0.681
0.808
0.748
(5)
Itraconazole 200
Cyclosporin
2.27
0.681
0.822
0.954
(5)
Ketoconazole 400
Cyclosporin
4.25
0.681
1.123
0.98
(5)
Verapamil 240
Cyclosporin
1.65
0.681
0.578
0.687
(16)
¥
§
Regular Strength
Double Strength
-4-
Supplemental table III. Predicted AUC ratios greater than 5
SUBSTRATE
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Buspirone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Dronedarone
Felodipine
Felodipine
Felodipine
Felodipine
Felodipine
Felodipine
Felodipine
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Lovastatin
Midazolam
Midazolam
Midazolam
Midazolam
Midazolam
Midazolam
Midazolam
Midazolam
Midazolam
Midazolam
Nisoldipine
Nisoldipine
Nisoldipine
INHIBITOR
Boceprevir
Clarithromycin
Erythromycin
Grapefruit DS
Itraconazole
Ketoconazole
Nefazodone
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Boceprevir
Clarithromycin
Grapefruit DS
Itraconazole
Ketoconazole
Nefazodone
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Grapefruit DS
Itraconazole
Ketoconazole
Ritonavir
Telaprevir
Telithromycin
Voriconazole
Boceprevir
Clarithromycin
Diltiazem
Erythromycin
Grapefruit DS
Itraconazole
Ketoconazole
Nefazodone
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Boceprevir
Clarithromycin
Grapefruit DS
Itraconazole
Ketoconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Boceprevir
Clarithromycin
Grapefruit DS
AUC ratio
7.2
7.8
5.3
12.8
16.8
50.3
6.3
50.3
7.8
25.2
10.1
33.6
5.8
6.1
8.7
10.3
16.8
5.2
16.8
6.1
12.7
7.4
14.5
5.8
6.5
8.4
8.4
7.3
5.3
7.8
7.6
8.3
5
5.5
14.3
19.6
91
6.6
91
8.3
32.3
11
47.7
5
5.3
7
7.9
11.2
11.2
5.3
9.3
6.1
10.2
6.1
6.4
9.4
SUBSTRATE
Nisoldipine
Nisoldipine
Nisoldipine
Nisoldipine
Nisoldipine
Nisoldipine
Nisoldipine
Nisoldipine
Quietapine
Quietapine
Quietapine
Quietapine
Quietapine
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Sirolimus
Sirolimus
Sirolimus
Sirolimus
Tacrolimus
Tacrolimus
Tacrolimus
Tacrolimus
Tacrolimus
Tacrolimus
Tacrolimus
Tacrolimus
Tacrolimus
Ticagrelor
Ticagrelor
Ticagrelor
Ticagrelor
Ticagrelor
Ticagrelor
Triazolam
Triazolam
Triazolam
Triazolam
Triazolam
Triazolam
Triazolam
Triazolam
Triazolam
Triazolam
-5-
INHIBITOR
Itraconazole
Ketoconazole
Nefazodone
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Itraconazole
Ketoconazole
Ritonavir
Telaprevir
Voriconazole
Boceprevir
Clarithromycin
Diltiazem
Erythromycin
Grapefruit DS
Itraconazole
Ketoconazole
Nefazodone
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Itraconazole
Ketoconazole
Ritonavir
Voriconazole
Clarithromycin
Grapefruit DS
Itraconazole
Ketoconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Grapefruit DS
Itraconazole
Ketoconazole
Ritonavir
Telaprevir
Voriconazole
Boceprevir
Clarithromycin
Grapefruit DS
Itraconazole
Ketoconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
AUC ratio
11.4
20.2
5.4
20.2
6.4
14.5
7.9
16.9
5.2
6.3
6.3
5.7
6
7.6
8.3
5
5.5
14.3
19.6
91
6.6
91
8.3
32.3
11
47.7
5
5.9
5.9
5.7
5
6.5
7.4
10.1
10.1
5
8.5
5.8
9.2
5.3
5.8
7.2
7.2
6.4
6.8
5.2
5.5
7.5
8.6
12.6
12.6
5.5
10.2
6.5
11.3
Supplemental table IV. Interactions of substrates with known intestinal availability with
grapefruit juice (regular strength).
Victim
Fg a
Fh b
CR3A4
AUC ratio c
IR3A4 d
drug
Predicted
AUC ratio
with IR3A4
= 0.51
Nisoldipine
0.11
NA
0.97
1.76
0.45
1.98
Tacrolimus
0.14
0.97
0.91
2.10
0.58
1.87
Felodipine
0.45
0.60
0.87
2.00
0.58
1.80
Midazolam
0.51
0.47
0.91
2.00
0.55
1.87
Nifedipine
0.74
0.46
0.72
1.35
0.36
1.58
Triazolam
0.75
NA
0.93
1.50
0.35
1.90
Alprazolam
0.94
0.95
0.75
1.12
0.14
1.62
a
intestinal availability, from reference (17, 18)
b
hepatic availability, from reference (19)
c
AUC ratio for interactions with grapefruit juice. All values were taken from (20). For
felodipine, the mean of 17 studies was used.
d
IR3A4 of grapefruit juice calculated by equation 3
-6-
References
1.
Guest EJ, Rowland-Yeo K, Rostami-Hodjegan A, Tucker GT, Houston JB, Galetin A.
Assessment of algorithms for predicting drug-drug interactions via inhibition mechanisms:
comparison of dynamic and static models. Br J Clin Pharmacol. janv 2011;71(1):72‑87.
2.
Foti RS, Rock DA, Wienkers LC, Wahlstrom JL. Selection of Alternative CYP3A4
Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo
Simulation. Drug Metab Dispos. 6 janv 2010;38(6):981‑987.
3.
Veronese ML, Gillen LP, Burke JP, Dorval EP, Hauck WW, Pequignot E, et al.
Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice. J
Clin Pharmacol. août 2003;43(8):831‑839.
4.
Watanabe H, Kosuge K, Nishio S, Yamada H, Uchida S, Satoh H, et al.
Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in
patients with hypercholesterolemia and hypertension. Life Sci. 3 déc 2004;76(3):281‑292.
5.
Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on
oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. févr 2000;38(2):111‑180.
6.
Ohashi K, Sudo T, Sakamoto K, Tateishi T, Fujimura A, Kumagai Y, et al. The
influence of pretreatment periods with diltiazem on nifedipine kinetics. J Clin Pharmacol.
mars 1993;33(3):222‑225.
7.
Uesawa Y, Mohri K. Relationship between lipophilicities of 1,4-dihydropyridine
derivatives and pharmacokinetic interaction strengths with grapefruit juice. Yakugaku Zasshi.
janv 2008;128(1):117‑122.
8.
alone
Saseen JJ, Carter BL, Brown TE, Elliott WJ, Black HR. Comparison of nifedipine
and
with
diltiazem
or
verapamil
1996;28(1):109‑114.
-7-
in
hypertension.
Hypertension.
juill
9.
Ragueneau-Majlessi I, Boulenc X, Rauch C, Hachad H, Levy RH. Quantitative
correlations among CYP3A sensitive substrates and inhibitors: literature analysis. Curr Drug
Metab. déc 2007;8(8):810‑814.
10.
Bailey DG, Malcolm J, Arnold O, David Spence J. Grapefruit juice-drug interactions.
Br J Clin Pharmacol. août 1998;46(2):101‑110.
11.
Cardiello PG, Samor T, Burger D, Hoetelmans R, Mahanontharit A, Ruxrungtham K,
et al. Pharmacokinetics of lower doses of saquinavir soft-gel caps (800 and 1200 mg twice
daily) boosted with itraconazole in HIV-1-positive patients. Antivir Ther. juin
2003;8(3):245‑249.
12.
Sádaba B, López de Ocáriz A, Azanza JR, Quiroga J, Cienfuegos JA. Concurrent
clarithromycin
and
cyclosporin
A
treatment.
J
Antimicrob
Chemother.
sept
1998;42(3):393‑395.
13.
Jones TE, Morris RG, Mathew TH. Diltiazem-cyclosporin pharmacokinetic
interaction--dose-response relationship. Br J Clin Pharmacol. nov 1997;44(5):499‑504.
14.
Gupta SK, Bakran A, Johnson RW, Rowland M. Cyclosporin-erythromycin
interaction in renal transplant patients. Br J Clin Pharmacol. avr 1989;27(4):475‑481.
15.
Schwarz UI, Johnston PE, Bailey DG, Kim RB, Mayo G, Milstone A. Impact of citrus
soft drinks relative to grapefruit juice on ciclosporin disposition. Br J Clin Pharmacol. oct
2006;62(4):485‑491.
16.
Sabaté I, Griñó J, Castelao AM, Ortolá J. Evaluation of cyclosporin-verapamil
interaction, with observations on parent cyclosporin and metabolites. Clin Chem. oct
1988;34(10):2151.
-8-
17. Gertz M, Harrison A, Houston JB, Galetin A. Prediction of human intestinal first-pass
metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug
Metab Dispos. 2010 Jul;38(7):1147-58.
18. Gertz M, Houston JB, Galetin A. Physiologically based pharmacokinetic modeling of
intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction. Drug
Metab Dispos. 2011 Sep;39(9):1633-42.
19. Kadono K, Akabane T, Tabata K, Gato K, Terashita S, Teramura T. Quantitative
prediction of intestinal metabolism in humans from a simplified intestinal availability model
and empirical scaling factor. Drug Metab Dispos. 2010 Jul;38(7):1230-7.
20. Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ. The effect of grapefruit juice on
drug disposition. Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):267-86.
-9-