Quantitative Prediction of the Impact of Drug Interactions and Genetic Polymorphisms on Cytochrome P450 2C9 Substrate Exposure

Transcription

1 Clinical Pharmacokinetics Quantitative Prediction of the Impact of Drug Interactions and Genetic Polymorphisms on Cytochrome P450 2C9 Substrate Exposure Anne-Charlotte Castellan, Michel Tod, François Gueyffier, Mélanie Audars, Fredéric Cambriels, Behrouz Kassaï, Patrice Nony, and the Genophar II Working Group Anne-Charlotte Castellan Université de Lyon, F-69000, Lyon, Université Lyon 1, CNRS UMR5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Modélisation et Evaluation des Thérapeutiques, 7 rue Guillaume Paradin Lyon, France castellan_charlotte@yahoo.fr Electronic Supplementary Material

2 Appendix 1, part 1: Main characteristics of studies used for the estimation of initial values of CR 2C9 (fractional contribution of CYP2C9 to oral clearance in vivo) for drugs metabolized by CYP2C9 Drug (dose value) Single /Multiple Number of subjects (a) Healthy/Patients Sampling CR 2C9 Ref. dose/steady state S-Acenocoumarol (8mg) Single 6 (6) healthy rich 0.99 [1] Benzbromarone (100mg) Single 20 (16) healthy Rich 0.76 [2] Celecoxib NA 13(10) healthy NA 0.95 [3] Diclofenac (50mg) Single 20 (11) healthy Rich 0.1 [4] Fluindione (20 mg) Multiple 24(NA) healthy Rich 0.76 [5] Flurbiprofen (50 mg) Single 15(NA) healthy Rich 0.94 [6] 3R-5S Fluvastatin (40 mg of Single 26(8) healthy Rich 0.75 [7] racemic fluvastatin) 3S-5R Fluvastatin (40 mg of Single 26(8) healthy 0.89 [7] racemic fluvastatin) Rich Glimepiride (0.5 mg) Single 20(11) healthy Rich 1 [8] Glyburide (3.5 mg) Single 21(15) healthy Rich 0.63 [9] R-Ibuprofen (400 mg of racemic ibuprofen) S-Ibuprofen (400 mg of racemic ibuprofen) Single 130(70) healthy Rich 0.56 [10] Single 130(70) healthy Rich 0.92 [10] Indomethacin (b) Not applicable Not applicable Not applicable Not applicable 0.5 [11] Irbesartan Multiple 1087(1087) hypertensive patients 0.88 [12]

3 Appendix 1, part 2: Main characteristics of studies used for the estimation of initial values of CR 2C9 (fractional contribution of CYP2C9 to oral clearance in vivo) for drugs metabolized by CYP2C9 Drug (dose) Single /Multiple Number of subjects (a) Healthy/Patients Sampling CR Ref. dose/steady state Lornoxicam single 23(20) healthy rich 1 [13] Losartan(NA) NA 1796 NA NA 0.33 [14] Naproxen (b) Not applicable Not applicable Not applicable Not applicable 0.2 [11] Nateglinide (180 mg) Single 23(8) healthy rich 0.54 [15] Phenobarbital Steady state 79(5) epileptic NA 1 [16] Phenprocoumon-S (12 mg) single 26(NA) healthy NA 0.39 [17] Phenytoin (100 mg) Multiple 31(22) healthy rich 0.83 [18] Piroxicam (20 mg) Single 35(26) healthy rich 0.85 [19] Tenoxicam (b) Not applicable Not applicable Not applicable Not applicable 0.3 [11] Tolbutamide (500 mg) single 23(9) Healthy rich 0.94 [20] Torsemide (10 mg) single 36(14) healthy rich 0.93 [21] (a) Two numbers are given in this column: - the first one corresponds to the total number of subjects included in the study, - the number into brackets corresponds to the number of subjects used for the estimation of CR. (b) For indomethacine, naproxen and tenoxicam, CRs estimations were based on in vitro data and clinical ADME data (fraction of dose recovered as metabolites). For more details, please refer to the article of Rodrigues [11]. NA: Not available

4 References for appendix 1 1. Thijssen, H.H. and B. Ritzen, Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype. Clin Pharmacol Ther, (1): p Uchida, S., et al., Benzbromarone pharmacokinetics and pharmacodynamics in different cytochrome P450 2C9 genotypes. Drug Metab Pharmacokinet. 25(6): p Sandberg, M., et al., Accumulation of celecoxib with a 7-fold higher drug exposure in individuals homozygous for CYP2C9*3. Clin Pharmacol Ther, : p Kirchheiner, J., et al., Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans. Br J Clin Pharmacol, (1): p Verstuyft, C., et al., A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on fluindione and acenocoumarol during induction therapy. Clin Pharmacokinet. 51(1): p Lee, C.R., et al., Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Eur J Clin Pharmacol, (12): p Kirchheiner, J., et al., Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5Rfluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther, (2): p Niemi, M., et al., Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther, (3): p Kirchheiner, J., et al., Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther, (4): p Garcia-Martin, E., et al., Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther, (2): p Rodrigues, A.D., Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug Metab Dispos, (11): p Hong, X., et al., CYP2C9*3 allelic variant is associated with metabolism of irbesartan in Chinese population. Eur J Clin Pharmacol, : p Guo, Y., et al., Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans. Drug Metab Dispos, (6): p Bae, J.W., et al., Frequency of CYP2C9 alleles in Koreans and their effects on losartan pharmacokinetics. Acta Pharmacol Sin. 32(10): p

5 15. Kirchheiner, J., et al., Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers. Clin Pharmacokinet, (4): p Goto, S., et al., Population estimation of the effects of cytochrome P450 2C9 and 2C19 polymorphisms on phenobarbital clearance in Japanese. Ther Drug Monit, (1): p Kirchheiner, J., et al., Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics, (1): p Caraco, Y., M. Muszkat, and A.J. Wood, Phenytoin metabolic ratio: a putative marker of CYP2C9 activity in vivo. Pharmacogenetics, (7): p Perini, J.A., et al., Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam. Clin Pharmacol Ther, (4): p Kirchheiner, J., et al., Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics, (2): p Vormfelde, S.V., et al., CYP2C9 polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide. Clin Pharmacol Ther, (6): p

6 Appendix 2, part 1: Main characteristics of studies used in the genetic model of our work for the external validation. The FA value (CYP2C9 s fraction of activity) associated to the genotype is specified. Single Dose Number Healthy/Patients Sampling Genotype Drug dose/multiple of Observed AUC (number of FA dose/steady state subjects ratio subjects) Ref. Celecoxib Multiple 200 mg 24 healthy rich *1/*3 (4) [1] Celecoxib Multiple 200 mg 24 healthy rich *2/*2 (2) [1] Celecoxib Multiple 200 mg 24 healthy rich *1/*2 (6) [1] Celecoxib Steady state 250 mg/m2 4 Children with solid tumor NA *1/*2 (1) [2] R-Ibuprofen Single 600 mg 21 healthy Rich *1/*3 (4) [3] R-Ibuprofen Single 600 mg 21 healthy Rich *2/*2 (2) [3] R-Ibuprofen Single 600 mg 21 healthy Rich *1/*2 (4) [3] R-Ibuprofen Single 600 mg 21 healthy Rich *2/*3 (3) [3] S-Ibuprofen Single 600 mg 21 healthy Rich *1/*2 (4) [3] S-Ibuprofen Single 600 mg 21 healthy Rich *2/*3 (3) [3] S-Ibuprofen Single 600 mg 21 healthy Rich *1/*3 (4) [3] S-Ibuprofen Single 600 mg 21 healthy Rich *2/*2 (2) [3] Lornoxicam Single 8 mg 18 healthy Rich *1/* [4] Losartan Steady-state healthy Rich *1/*2 (2) [5]

7 Appendix 2, part 2: Main characteristics of studies used in the genetic model of our work for the external validation. The FA value (CYP2C9 s fraction of activity) associated to the genotype is specified. Drug Single Dose Number Healthy/Patients Sampling Genotype FA Observed AUC dose/multiple of (number of ratio Ref. dose/steady state subjects subjects) Losartan single 25 mg 7 healthy Rich *1/*3 (3) [6] Phenytoin steady state Range: 36 epileptic sparse *1/*2 (9) [7] 150 and 225 mg Phenytoin steady state Range: 36 epileptic sparse *1/*3 (9) [7] 150 and 275 mg Phenytoin steady state Mean : 36 epileptic sparse *2/*3 (2) [7] 150 mg Phenytoin steady state Range: 36 epileptic sparse *2/*2 (3) [7] 175 and 275 mg Tenoxicam single 20 mg 662 healthy rich *1/*3 (5) [8] Tolbutamide single 500 mg 15 healthy rich *1/*2 (5) [9] Tolbutamide single 500 mg 15 healthy rich *1/*3 (5) [9] Tolbutamide single 500 mg 18 healthy rich *1/*3 (6) [10]

8 Appendix 2, part 3 Main characteristics of studies used in the genetic model of our work for the external validation. The FA value (CYP2C9 s fraction of activity) associated to the genotype is specified. Drug Single Dose Number Healthy/Patients Sampling Genotype FA Observed AUC dose/multiple of (number of ratio Ref. dose/steady subjects subjects) state S-Warfarin Steady state NA 156 Patients NA *1/*3 (NA) [11]

9 References for appendix 2 1. Brenner, S.S., et al., Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib. Clin Pharmacokinet, (3): p Stempak, D., letter to editor: Cytochrome P450 2C9 genotype: Impact on celecoxib safety and pharmacokinetics in a pediatric patient. Clinical Pharmacology and therapeutics, Kirchheiner, J., et al., Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin Pharmacol Ther, (1): p Zhang, Y., et al., Lornoxicam pharmacokinetics in relation to cytochrome P450 2C9 genotype. Br J Clin Pharmacol, (1): p Fischer, T.L., et al., Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers. Clin Pharmacol Ther, (3): p Sekino, K., et al., Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects. Eur J Clin Pharmacol, (8-9): p van der Weide, J., et al., The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics, (4): p Vianna-Jorge, R., et al., CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians. Clin Pharmacol Ther, (1): p Lee, C.R., et al., Evaluation of cytochrome P4502C9 metabolic activity with tolbutamide in CYP2C91 heterozygotes. Clin Pharmacol Ther, (5): p Shon, J.H., et al., Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans. Pharmacogenetics, (2): p

10 11. Loebstein, R., et al., Interindividual variability in sensitivity to warfarin--nature or nurture? Clin Pharmacol Ther, (2): p

11 Appendix 3, part 1. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Number Victim drug Interacting drug Single dose/ multiple dose/ Sampling of Healthy/Patients steady state subjects AUC ratio Use Ref. Acenocoumarol Piroxicam Multiple dose Acenocoumarol (4 mg of racemic (40 mg) Single dose piroxicam acenocoumarol) 8 healthy NA 1.47 External validation [1] R-Acenocoumarol Lornoxicam (10 mg of racemic Multiple dose 6 healthy NA 1.06 External validation [2] (16 mg/d) acenocoumarol) S-Acenocoumarol Piroxicam Multiple dose Acenocoumarol (4mg of racemic (40 mg) Single dose piroxicam acenocoumarol) 8 healthy NA 1.15 IR calculation [1] S-Acenocoumarol Lornoxicam (10 mg of racemic Multiple dose 6 healthy NA 1.24 IR calculation [2] (16 mg/d) acenocoumarol) Cyclophosphamide Fluconazole Single dose cyclophosphamide (median dose : 1050 (5 mg/kg/d) Multiple dose fluconazole mg/m²) 9 children rich 1.29 CR calculation [3]

12 Appendix 3, part 2. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Single dose/ multiple dose/ Number of Healthy/Patients Sampling Victim drug Interacting drug steady state subjects AUC ratio Use Ref. Celecoxib (NA) Celecoxib Celecoxib (200 mg) Diclofenac (25 mg) Diclofenac (25 mg) Diclofenac (50 mg) Diclofenac (50 mg) Diclofenac (50 mg) Fluconazole (200 mg/d) Fluconazole (200 mg) Rifampicine (600 mg/d) Fluvastatine (40 mg) Fluvastatine (40 mg) Tolbutamide (500 mg) Ibuprofen (400 mg) Fluvastatin (40 mg) NA NA NA NA 1.34 External validation [4] NA NA NA NA 2.3 External validation [5] single dose Celecoxib multiple dose Rifampicne 12 healthy rich 0.35 External validation [6] multiple dose Diclofenac multiple dose Fluvastatine 14 healthy NA 1.3 External validation [7] multiple dose Diclofenac multiple dose Fluvastatin 14 healthy Rich 1.25 External validation [8] single dose Diclofenac single dose Tolbutamide 12 healthy rich 1 IR calculation [9] single dose Diclofenac single dose Ibuprofen 12 healthy rich 0.99 IR calculation [9] single dose Diclofenac single dose Fluvastatin 12 healthy rich 1.07 External validation [9]

13 Appendix 3, part 3. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Victim drug Interacting Single dose/ multiple dose/ Number of Healthy/Patients Sampling drug steady state subjects AUC ratio Use Ref Flurbiprofen Fluconazole single dose Flurbiprofen (100 mg) (200 mg) single dose fluconazole 14 healthy rich 1.82 IR calculation [10] Flurbiprofen Fluconazole single dose Flurbiprofen (50 mg (200 mg/d) multiple dose Fluconazole 11 healthy rich 2 External validation [11] Flurbiprofen (50 mg) Fluvastatin Fluvastatin Fluvastatin (40 mg) Fluvastatin (80 mg) Fluvastatin Fluconazole (400 mg/d) Tolbutamide (500 mg) Glibenclamide (2.5 mg) Fluconazole (400 mg) Clopidogrel (75 mg) Rifampicin (600 mg/d) single dose Flurbiprofen multiple dose Fluconazole 11 healthy rich 3.2 External validation [11] single and multiple dose NA NA NA 1 External validation [12] single and multiple dose NA NA NA 1 IR calculation [12] multiple dose Fluconazole 12 healthy NA 1.84 External validation single dose Fluvastatin [13] steady-state NA healthy NA 1 IR calculation [14] NA NA NA NA 0.5 IC calculation [7]

14 Appendix 3, part 4. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Interacting Victim drug drug Fluvastatin Diclofenac (40 mg) (50 mg) Glibenclamide Fluvastatin (NA) (40 mg) Glibenclamide Fluvastatin (NA) (40 mg/d) Glibenclamide Simvastatin (NA) (20 mg) Glibenclamide Clarithromycine (0.87 mg) (250 mg) Rifampicin Glibenclamide (600 mg/d) Glimepiride Fluconazole (0.5 mg) (200 mg/d) Glimepiride Rifampicin (1 mg) (600 mg/d) Single dose/ multiple dose/ steady state single dose Fluvastatin Single dose Diclofenac NA Number of Sampling Healthy/Patients subjects AUC ratio Use Ref 12 healthy rich 1.08 IR calculation [9] 16 healthy NA 1.16 External validation [12] NA 16 healthy NA 1.21 External validation [12] NA 16 healthy NA 1.2 External validation [12] single dose glibenclamide multiple dose 12 NA NA 1.35 IR calculation [15] Clarithromycine single dose Glibenclamide multiple dose Rifampicin 10 healthy NA 0.61 External validation [16] single dose Glimepiride multiple dose Fluconazole 12 healthy NA 2.38 IR calculation [17] single dose Glimepiride multiple dose Rifampicin 10 healthy NA 0.34 External validation [18]

15 Appendix 3, part 5. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Victim drug Interacting Single dose/ multiple dose/ drug steady state Glimepiride Gemfibrozil multiple dose Glimiperide (0.5 mg) (600 mg) single dose Gemfibrozil R-Ibuprofen Fluconazole Single dose Ibuprofen (400 mg racemic (200 mg/d) Multiple dose Fluconazole Ibuprofen) R-Ibuprofen Voriconazole Single dose Ibuprofen (400 mg racemic (600 mg) Multiple dose Voriconazole Ibuprofen) S-Ibuprofen Fluconazole Single dose Ibuprofen (400 mg racemic (200 mg/d) Multiple dose Fluconazole Ibuprofen) S-Ibuprofen (400 mg Voriconazole Single dose Ibuprofen racemic Ibuprofen) (600 mg) Multiple dose Voriconazole Irbesartan Fluconazole multiple dose Irbesartan (150 mg/d) (300 mg/d) multiple dose Fluconazole Losartan Bucolome (300 multiple dose Losartan (25 mg/d) mg/d) multiple dose Bucolome Number Healthy/Patients Sampling of subjects AUC ratio Use Ref 10 healthy NA 1.23 IR calculation [19] 12 healthy rich 1.13 External validation [20] 12 healthy rich 1.17 External validation [20] 12 healthy rich 1.83 External validation [20] 12 healthy rich 2.05 IR calculation [20] 15 healthy rich 1.63 External validation [21] 6 healthy rich 1.68 External validation [22]

16 Appendix 3, part 6. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Interacting Victim drug drug Losartan Fluconazole (100 mg/d) (200 mg/d) Losartan Fluconazole (50 mg) (200 mg/d) Losartan Rifampicin (600 (50 mg/d) mg/d) Losartan Fluvastatin (40 (50 mg/d) mg/d) Losartan Phenytoin (300 (50 mg/d) mg/d) Meloxicam Voriconazole (15 mg) (800 mg) Nateglinide Fluconazole (30 mg/d) (200 mg) Nateglinide Rifampicin (NA) (600 mg/d) Single dose/ multiple dose/ Number Healthy/Patients Sampling AUC Use Ref steady state of subjects ratio multiple dose Losartan 16 healthy rich 1.69 External validation multiple dose Fluconazole [23] single dose Losartan 11 healthy NA 1.27 External validation multiple dose Fluconazole [24] Steady state 10 healthy NA 0.69 External validation [25] Steady state 13 healthy rich 1 External validation [26] Steady state 16 healthy rich 1.29 IR calculation [27] single dose Meloxicam 12 healthy rich 1.47 CR calculation multiple dose Voriconazole [28] single dose nateglinide 10 healthy NA 1.47 External validation multiple dose Fluconazole [29] NA NA NA NA 0.76 External validation [30]

17 Appendix 3, part 7. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Interacting Victim drug drug Fluconazole Nateglinide (400 mg) Nateglinide Sulfinpyrazone (120 mg) (400 mg/d) R-Phenprocoumon Lornoxicam (16 (9 mg racemic mg/d) phenprocoumon) S-Phenprocoumon Lornoxicam (16 (9 mg racemic mg/d) phenprocoumon) Fluoxetine (20 Phenytoin mg/d) Phenytoin Losartan (100 mg/d) (50 mg/d) Phenytoin Omeprazole (300 mg) (40 mg/d) Single dose/ multiple dose/ Number of Healthy/Patients Sampling steady state subjects AUC ratio Use Ref NA NA NA NA 1.48 External validation [30] single dose Nateglinide 18 healthy rich multiple dose 1.28 External validation sulfinpyrazone [31] single dose phenprocoumon multiple dose lornoxicam 6 healthy rich 1.12 External validation [32] single dose phenprocoumon multiple dose lornoxicam 6 healthy 1.24 External validation [32] Steady state 2 patient Sparse 3.2 IR calculation (monitoring) [33] Steady state 16 healthy rich 1 IR calculation [27] single dose Phenytoin 10 healthy rich 1.24 IR calculation multiple dose Omeprazole [34]

18 Appendix 3, part 8. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Victim drug Single dose/ multiple dose/ Number Healthy/Patients Sampling Interacting AUC steady state of drug ratio subjects Use Ref single dose Phenytoin Phenytoin (300 mg) Voriconazole (800 mg/d) multiple dose Voriconazole 21 healthy rich 1.81 IR calculation [35] Phenytoin Rifampicin multiple dose Phenytoin (100 mg) (600 mg/d) multiple dose Rifampicin 6 patient rich 0.5 External validation [36] Phenytoin Sulfaphenazole single dose Phenytoin (NA) (1 g/d) single dose Sulfaphenazole NA NA NA 3 External validation [37] Phenytoin Sulfamethizole Single dose phenytoin (NA) (600 mg/d) Single dose Sulfamethizole NA NA NA 1.56 External validation [37] Phenytoin Fluconazole multiple dose Phenytoin (250 mg) (200 mg) steady state Fluconazole 12 healthy NA 1.75 External validation [38] Phenytoin Fluconazole single dose Phenytoin (250 mg) (400 mg/d) Multiple dose Fluconazole 9 healthy rich 1.33 External validation [39]

19 Appendix 3, part 9. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Interacting Victim drug drug Phenytoin Sertraline (300 mg) (200 mg/d) Phenytoin Valproate (600 mg) (800 mg/d) Rosuvastatin Fluconazole (80 mg) (200 mg) Sulfamethoxazole Fluconazole (NA) (400 mg/d) Tolbutamide Fluconazole (NA) (100 mg/d) Tolbutamide Fluvastatin (NA) (40 mg/d) Irbesartan (300 Tolbutamide mg) Tolbutamide Sulfaphenazole (500 mg) (1 g/d) Single dose/ multiple dose/ Number of Healthy/Patients Sampling steady state subjects AUC ratio Use Ref Steady state 16 healthy NA 1.19 External validation [40] single dose Phenytoin multiple dose Valproate 12 healthy NA 1.18 External validation [41] single dose Rosuvastatin steady state Fluconazole 14 healthy rich 1.14 CR calculation [42] NA 6 healthy NA 1.35 CR calculation [43] single dose Tolbutamide multiple dose Fluconazole 12 healthy rich 1.5 External validation [44] NA NA NA NA 1.23 IR calculation [12] multiple 18 healthy rich 1.05 IR calculation [21] multiple dose Tolbutamide single dose sulfaphenazole 6 healthy NA 5.3 IR calculation [45]

20 Appendix 3, part 10. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Victim drug Single dose/ multiple dose/ Number Healthy/Patients Sampling Interacting AUC steady state of drug ratio subjects Use Ref Tolbutamide Sertraline single dose Tolbutamide (1000 mg) (200 mg/d) steady state Sertraline 25 healthy rich 1.19 IR calculation [46] Tolbutamide (a) Sulfamethizole Not Not applicable (600 mg/d) applicable Not applicable Not applicable 1.62 IR calculation [47] Tolbutamide Diclofenac single dose Tolbutamide (500 mg) (50 mg) single dose Diclofenac 12 healthy rich 1.01 External validation [9] Torasemide Irbesartan steady state Torasemide (100 mg/d) (150 mg/d) multiple dose Irbesartan 12 healthy rich 1.13 External validation [48] S-Warfarin Miconazole single dose Warfarin S (0.75 mg/kg per d (125 mg/d) multiple dose Miconazole racemic Warfarin) 6 healthy NA 4.72 IR calculation [49] S-Warfarin Irbesartan multiple dose Warfarin ( mg/d (300 mg/d) multiple dose Irbesartan racemic Warfarin) 16 healty rich 1 External validation [50] Zafirlukast Warfarin S (80 mg) NA NA NA NA 1.63 IR calculation [51]

21 Appendix 3, part 11. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Victim drug Single dose/ multiple dose/ Number Healthy/Patients Sampling Interacting AUC steady state of drug ratio subjects Use Ref S-Warfarin Bosentan single dose Warfarin (26 mg racemic (1000 mg/d) steady state Bosentan Warfarin) 12 healthy rich 0.71 IC calculation [52] S-Warfarin Fluconazole (NA) (400 mg/d) NA 6 healthy NA 2.84 IR calculation [53] Bucolome S-Warfarin (300 mg/d) Steay state 21 patients sparse 6.2 IR calculation [54] S-Warfarin Bucolome (mean : 4mg/d steady state 25 patient sparse 6 External validation [55] (300 mg/d) racemic Warfarin) Warfarin S Benzbromarone (mean : 2.5 mg/d steady state 13 patient sparse 2.2 IR calculation [56] (50 mg/d) racemic Warfarin) S-Warfarin Sulfinpyrazone single dose Warfarin (1.5 mg/kg racemic (400 mg/d) multiple dose Sulfinpyrazone Warfarin) 6 healthy NA 1.93 External validation [57]

22 Appendix 3, part 12. Main characteristics of studies used in the DDI part of our work. Published AUC ratios are reported. The use of the observed data into the model is specified: IR (Inhibition Ratio), IC (apparent increase in clearance), CR (fractional contribution of CYP2C9 to oral clearance in vivo) calculation or external validation. Victim drug Interacting drug Single dose/ multiple Number Healthy/Patients Sampling dose/ steady state of subjects AUC ratio Use Ref S-Warfarin Sulfinpyrazone (NA) (400 mg/d) NA 6 healthy NA 1.7 IR calculation [58] S-Warfarin Fluvastatin single dose Warfarin (10 mg of racemic (80 mg/d) steady state Fluvastatin Warfarin) 18 healthy rich 1.27 External validation [59] (a) IR was calculated based on in vitro data

23 References for appendix 3 1. Bonnabry, P., et al., Stereoselective interaction between piroxicam and acenocoumarol. Br No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics J Clin Pharmacol, (6): p Masche, U.P., et al., No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics. Eur J Clin Pharmacol, (11): p Yule, S.M., et al., The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Dispos, (3): p Davies, N.M., et al., Clinical pharmacokinetics and pharmacodynamics of celecoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet, (3): p VIDAL Jayasagar, G., et al., Influence of rifampicin pretreatment on the pharmacokinetics of celecoxib in healthy male volunteers. Drug Metabol Drug Interact, (4): p Scripture, C.D. and J.A. Pieper, Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet, (4): p Transon, C., et al., In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)-fluvastatin. Clin Pharmacol Ther, (4): p Andersson, T.B., et al., An evaluation of the in vitro metabolism data for predicting the clearance and drug-drug interaction potential of CYP2C9 substrates. Drug Metab Dispos, (7): p Greenblatt, D.J., et al., Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies. Clin Pharmacol Ther, (1): p Kumar, V., et al., Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos, (7): p Appel, S., et al., Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with noninsulin-dependent diabetes mellitus. Am J Cardiol, (2): p. 29A-32A. 13. Kantola, T., et al., Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol, (3): p Ayalasomayajula, S.P., et al., Effect of clopidogrel on the steady-state pharmacokinetics of fluvastatin. J Clin Pharmacol, (5): p Lilja, J.J., et al., Effects of clarithromycin and grapefruit juice on the pharmacokinetics of glibenclamide. Br J Clin Pharmacol, (6): p Niemi, M., et al., Effects of rifampin on the pharmacokinetics and pharmacodynamics of glyburide and glipizide. Clin Pharmacol Ther, (6): p

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