Supplemental Materials

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1 Supplemental Materials Evaluation of Ketoconazole and its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin and Itraconazole on 13 Clinically-Relevant Drug Transporters Lydia M.M. Vermeer, Caleb D. Isringhausen, Brian W. Ogilvie, and David B. Buckley 1

2 Figure 1 - OATP1B1 2

3 Figure 2 - OATP1B3 3

4 Figure 3 - OAT1 4

5 Figure 4 - OAT3 5

6 Figure 5 - OCT1 6

7 Figure 6 - OCT2 7

8 Figure 7 - MATE1 8

9 Figure 8 - MATE2-K 9

10 Figure 9 - P-gp 10

11 Figure 10 - BCRP 11

12 Figure 11 - BSEP 12

13 Figure 12 - Positive control inhibitors OATP1B1 OATP1B3 OAT1 OAT3 MATE1 MATE2-K 13

14 Figure 12 cont. - Positive control inhibitors OCT1 OCT2 P-gp BCRP MRP2 MRP3 14

15 Figure 12 cont. - Positive control inhibitors BSEP 15

16 Supplemental Table 1: Concentration Ranges CYP3A4 inhibitor Transporter OATP1B1 OATP1B3 OAT1 OAT3 OCT1 OCT2 MATE1 MATE2-K Ketoconazole 0.1, 0.3, 1, 3, 10, , 0.3, 1, 3, 10, , 0.3, 1, 3, 10, , 0.3, 1, 3, 10, , 0.3, 1, 3, 10, , , 1, 2 0.3, 1, 2 Itraconazole 0.03, 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, 10 Hydroxyitraconazole 0.01, 0.03, 0.1, 0.3, 1, , 0.03, 0.1, 0.3, 1, , 0.003, 0.01, 0.03, 0.1, 0.3 Keto-itraconazole 0.01, 0.03, 0.1, 0.3, 1, , 0.03, 0.1, 0.3, 1, , 0.03, 0.1, 0.3, 1, 3 N-deskalkyl itraconzole 0.001, 0.003, , 0.003, 0.01, 0.03, 0.1, , 0.003, , 0.003, 0.01, 0.03, 0.1, , 0.003, 0.01, 0.03, 0.1, , 0.003, , 0.003, , 0.003, 0.2 Clarithromycin 30, 50 30, 50 30, 50 30, 50 30, 50 30, 50 30, 50 30, 50 Ritonavir 0.03, 0.1, 0.3, 1, 3, 10 20, 30 20, 30 20, 30 20, 30 20, , 0.3, 1, 3, 10, , 0.3, 1, 3, 10, 20 16

17 Supplemental Table 2: Concentration Ranges CYP3A4 inhibitor Transporter P-gp BCRP MRP2 MRP3 BSEP Ketoconazole 0.1, , , , , 20 Itraconazole 0.03, 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, , 0.1, 0.3, 1, 3, 10 Hydroxyitraconazole 0.3, 1, 3 0.3, 1, 3 0.3, 1, 3 0.3, 1, 3 Keto-itraconazole 0.3, 1, 3 0.3, 1, 3 0.3, 1, 3 0.3, 1, 3 N-deskalkyl itraconzole 0.001, 0.003, , 0.003, 0.01, 0.03, 0.1, , 0.003, 0.01, 0.03, 0.1, , 0.003, 0.01, 0.03, 0.1, , 0.003, 0.01, 0.03, 0.1, 0.2 Clarithromycin 30, 50 30, 50 30, 50 30, 50 30, 50 Ritonavir 20, 30 20, 30 20, 30 20, 30 17

18 Supplemental Table 3: CYP3A inhibitors in clinical DDI studies Perpetrator Ketoconazole (highdose) Ketoconazole (highdose) Ketoconazole (low-dose) Clarithromycin (highdose) Ritonavir (low-dose) Itraconazole Itraconazole (oral solution) Hydroxyitraconazole (oral solution) Itraconazole (oral solution) Dose and regimen 400 mg qd 4 days 200 mg bid 1.5 to 10 days C max () C max,ss () [I] gut () Midazolam dose and regimen Max Midazolam AUCR Review PMID Primary PMID 2.82 NR 7.5 mg PO, day h NR Various fold UW DIDB NA mg qd 3 days 3.57 NR 1505 NA 200 mg qd 4 to 14 days 500 mg bid 7 days 250 mg bid days 100 mg bid days 200 mg qd 3-42 days 200 mg bid 142 days 200 mg bid 142 days Various fold UW DIDB NA NA (Ke reports 9.2- fold) UW DIDB Various fold UW DIDB NA (4 days) mg PO, day 0 and mg PO 3.6-fold NA NA (0.08 at 100 mg QD, 17 days) mg PO day Various fold UW DIDB 10.8 (with 200 mg qd 4 days) 2.32 NA 1134 NA NR 3.28 NA NA NA NA 1.15 NA 567 NR NR e.g.: UW DIDB NA Hydroxyitraconazole NA NA NA NA 100 mg qd 7 days Keto-itraconazole NA NA NA NA NA Clarithromycin (lowdose) N-desalkylitraconazole NA NA NA NA 18

19 Supplemental Equations 1 1. R value = 1 + (f u I in,max IC 50 ) Where: f u = fraction unbound of the inhibitor I in,max = estimated maximum inhibitor concentration at the inlet to the liver I in,max = C max + (k a Dose F af g Qh ) k a = absorption rate constant of the inhibitor (assumed 0.1) F a F g = fraction of the dose of inhibitor absorbed (assumed 1) C max = maximum systemic plasma concentration of inhibitor OATP1B1/ OATP1B3 2. [I] 1 IC 50 Where: [I] 1 = mean steady state total (free and unbound) C max following administration of highest proposed clinical dose of inhibitor P-gp, BCRP, BSEP, MRP2, MRP3, OATP1B1, OATP1B3, OCT1 3. [I] 2 IC 50 Where: [I] 2 = Dose of the inhibitor (in mol)/250 ml P-gp, BCRP, MRP2 4. Unbound C max IC I 1,unbound IC 50 OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K P-gp, BCRP 19