Article Figures & Data
Figures
- Fig. 1.
Comparison of TDI parameters obtained in HLM versus HHEP). (A) KI,u; (B) kinact; and (C) kinact/KI,u. Solid black lines represent unity, dotted and dashed lines represent 2-fold and 3-fold deviation from unity, and solid red line represents bias. Azithromycin, nelfinavir, terfenadine, paroxetine, and eplerenone are not shown in (A) and (B) because individual KI and kinact were not able to be determined.
- Fig. 2.
Predicted versus observed AUC ratios from mechanistic static Model 4 (A and B) and Simcyp modeling (C and D). (A and C) are results using human liver microsome–generated inactivation parameters, and (B and D) are results human hepatocyte–generated inactivation parameters. Solid black lines represent unity, dotted lines represent 2-fold and 3-fold deviation from unity, and red solid lines represent the bias.
- Fig. 3.
Model performance versus observed AUCR from mechanistic static Model 4 (A and B) and Simcyp modeling (C and D). (A and C) are results using human liver microsome–generated inactivation parameters, and (B and D) are results using human hepatocyte–generated inactivation parameters. Shaded area represents 0.5- to 2-fold criteria. Azi, azithromycin; Boc, boceprevir; Car, carfilzomib; Cla, clarithromycin; Con, conivaptan; Dil, diltiazem; Dis, disulfiram; Epl, eplerenone; Ery, erythromycin; Ima, imatinib; Mid, midostaurin; Nel IV, nelfinavir (IV midazolam); Nit, nitrendipine; Pan, panobinostat; Par, paroxetine; Ppv, propiverine; Pro, propranolol; Sim, simvastatin; Tab, tabimorelin; Tad, tadalafil; Tel, telaprevir; Tel IV, telaprevir (IV midazolam); Ter, terfenadine; Ver, verapamil.
- Fig. 4.
Classification of predicted (Pred) AUCR versus observed (Obs) AUCR using 1.25- and 2-fold cutoff criteria in mechanistic static models 1–4. Values in each section of the bar graphs represent the number of drugs that were predicted to be TP, TN, FP, or FN using liver microsome (A) or hepatocyte- (B) generated parameters.
- Fig. 5.
Classification of predicted (Pred) AUCR versus observed (Obs) AUCR using 1.25- and 2-fold cutoff criteria using Simcyp. Values in each section of the bar graphs represent the number of drugs that were predicted to be TP, TN, FP, or FN using HLM or HHEP generated parameters.
- Fig. 6.
Correlation of predicted AUC ratios (AUCR) from mechanistic static Model 4 and Simcyp modeling. (A) represents predictions using human liver microsome–generated inactivation parameters and (B) represents predictions using human hepatocyte–generated inactivation parameters. The solid black line represents unity.
Tables
Drug Name Inhibitor Dose Substrate Doseb Clinical Interaction (AUCR) Clinical Interaction Reference Azithromycin 500 mg once a day; 3 d 15 mg oral midazolam 1.23a (Yeates et al., 1996; Zimmermann et al., 1996) Boceprevir 800 mg three times a day; 6 d 4 mg oral midazolam 5.05 (FDA, 2011) Carfilzomib 27 mg/m2 i.v.; various 2 mg oral midazolam 1.10 (Wang et al., 2013) Clarithromycin 500 mg twice a day; 7 d 4 mg oral midazolam 6.69a (Gorski et al., 1998; Gurley et al., 2006; Gurley et al., 2008; Quinney et al., 2008; Prueksaritanont et al., 2017) Conivaptan 40 mg twice a day; 5 d 2 mg oral midazolamc 5.76 (FDA, 2005) Diltiazem 60 mg three times a day; 2 d 2 mg oral midazolam 3.93a (Backman et al., 1994; Friedman et al., 2011) Disulfiram 500 mg single dose 1 mg i.v. midazolam 1.05 (Kharasch et al., 1999) Eplerenone 100 mg once a day; 6 d 10 mg oral midazolam 0.96 (Cook et al., 2004) Erythromycin 500 mg three times a day; 7 d 4 mg oral midazolam 4.12a (Olkkola et al., 1993; Zimmermann et al., 1996) Imatinib 400 mg once a day; 7 d 40 mg oral simvastatin 2.92 (O'Brien et al., 2003) Midostaurin 100 mg single dose 4 mg oral midazolam 1.00 (Dutreix et al., 2013) Nelfinavir 1250 mg twice a day; 14 d 2 mg oral midazolam
1 mg i.v. midazolam4.29a
1.83(Kirby et al., 2011) Nitrendipine 20 mg single dose 0.07 mg/kg i.v. plus infusion midazolam 0.93 change in CL (Handel et al., 1988) Panobinostat 20 mg every other day; 15 d 5 mg oral midazolam 1.04 (Einolf et al., 2017) Paroxetine 20 mg once a day; 15 d 60 mg oral terfenadined 0.97 (Martin et al., 1997) Propiverine 15 mg twice a day; 7 d 2 mg oral midazolam 1.46 (Tomalik-Scharte et al., 2005) Propranolol 40 mg four times a day; 2 d 0.5 mg oral triazolam 0.89 (Friedman et al., 1988) Simvastatin 10 mg once a day; 14 d 15 ug/kg oral midazolam 1.24 (Kokudai et al., 2009) Tabimorelin 3 mg/kg once a day; 7 d 7.5 mg oral midazolam 1.93 (Zdravkovic et al., 2003) Tadalafil 10 mg once a day; 14 d 15 mg oral midazolam 0.90 (Ring et al., 2005) Telaprevir 750 mg three times a day; 16 d 2 mg oral midazolam
0.5 mg i.v. midazolam13.5
4.92(Garg et al., 2012) Terfenadine 120 mg once a day; 3 d 10 mg oral buspirone 1.19 (Lamberg et al., 1999) Verapamil 80 mg three times a day; 2 d 15 mg oral midazolam 2.92 (Backman et al., 1994) Reversible Inhibition Time-Dependent Inhibition Drug Name Kia fu,mic Ki,u KI (S.E.) fu,mic (%CV) KI,u kinact (S.E.) kinact/KI,u µM at 0.01 mg/mld µM µM at 0.3 mg/ml µM min−1 ml·min−1·µmol−1 Azithromycin >50.0 0.982 >49.1 NR 0.650 (9) NR NR 0.025 Boceprevir 11.9 0.990 11.8 13.8 (1.7) 0.766 (12) 10.6 0.304 (0.010) 28.8 Carfilzomib 2.19 0.964 2.11 1.18 (0.22) 0.473b 0.558 0.107 (0.007) 192 Clarithromycin 43.9 0.982 43.1 55.9 (13.4) 0.647 (16) 36.2 0.0812 (0.0086) 2.25 Conivaptan 4.14 0.929 3.84 1.04 (0.16) 0.303 (4) 0.315 0.329 (0.013) 1040 Diltiazem 20.3 0.986 20.0 1.90 (0.28) 0.696 (9) 1.32 0.0109 (0.0004) 8.24 N-desmethyl Diltiazemc ND ND ND 0.961 (0.115) ND 0.961 0.00954 (0.00027) 9.94 Disulfiramc 1.18 ND 1.18 16.4 (5.2) ND 16.4 0.129 (0.012) 7.87 Eplerenone >50.0 0.991 >49.5 202 (58) 0.779 (10) 157 0.0223 (0.0029) 0.142 Erythromycin 32.0 0.979 31.3 23.3 (3.3) 0.613 (38) 14.3 0.0557 (0.0025) 3.90 Imatinib 28.9 0.974 28.2 16.4 (4.9) 0.560 (15) 9.18 0.0348 (0.0029) 3.79 Midostaurin 2.79 0.267 0.740 0.360 (0.120) 0.0118 (29) 0.00425 0.0207 (0.0015) 4870 Nelfinavir 1.46 0.561 0.816 1.44 (0.45) 0.0408 (21) 0.0588 0.510 (0.057) 8680 Nitrendipine 1.37 0.960 1.32 10.4 (3.1) 0.444 (22) 4.62 0.0266 (0.0020) 5.76 Panobinostat 4.99 0.971 4.84 30.3 (6.8) 0.530 (9) 16.1 0.0436 (0.0027) 2.71 Paroxetine 13.4 0.833 11.2 49.4 (22.0) 0.143 (17) 7.06 0.0277 (0.0084) 3.92 Propiverine 8.05 0.961 7.74 1.71 (0.23) 0.451 (25) 0.771 0.0298 (0.0012) 38.7 Propranolol >50.0 0.978 >48.9 No TDI 0.594 (3) No TDI No TDI No TDI Simvastatin 0.146 0.651 0.095 NR 0.0585 (12) NR NR 0.195 Tabimorelin 8.30 0.973 8.08 1.98 (0.31) 0.547 (12) 1.08 0.0652 (0.0023) 60.2 Tadalafil 8.55 0.990 8.46 13.0 (1.7) 0.776 (4) 10.1 0.143 (0.004) 14.2 Telaprevir 11.6 0.992 11.5 0.644 (0.109) 0.806 (9) 0.519 0.108 (0.004) 208 Terfenadine 0.218 0.559 0.122 9.32 (5.85) 0.0405 (3) 0.377 0.0276 (0.0111) 73.2 Verapamil 12.9 0.979 12.6 2.80 (0.54) 0.610 (23) 1.71 0.0487 (0.0023) 28.5 %CV, percent coefficient of variation; ND, not determined (assume 1); NR, not reported (see data analysis section for the estimation of kinact/KI,u).
↵aCalculated as measured IC50/2.
bBased on in silico modeling.
cTotal values were reported since unbound fractions were not determined.
dfu,mic was calculated from fu,mic measured at 0.3 mg/ml (n = 3 to 4) using equation from (Austin et al., 2002).
Reversible Inhibition Time-Dependent Inhibition Drug Name Kia Kp,uub Ki,u KI (S.E.) KI,u kinact (S.E.) kinact/KI,u µM %CV µM µM µM min−1 ml·min−1·µmol−1 Azithromycin >25.0 5.70 (5) >143 51.2 (17.3) 292 0.0327 (0.0032) 0.112 Boceprevir 10.8 0.190 (0.5) 2.04 25.9 (10.7) 4.92 0.0978 (0.0161) 19.9 Carfilzomib 1.71 0.0160 (33) 0.0300 7.76 (2.26) 0.126 0.0289 (0.0020) 229 Clarithromycin 13.8 0.600 (7) 8.25 7.45 (2.06) 4.47 0.0112 (0.0007) 2.51 Conivaptan 1.27 1.70 (8) 2.16 0.634 (0.124) 1.08 0.0182 (0.0010) 16.9 Diltiazem 13.0 0.253 (10) 3.28 35.4 (6.6) 8.96 0.0217 (0.0010) 2.42 N-desmethyl Diltiazemc ND ND ND 2.96 (1.12) 2.96 0.0127 (0.0011) 4.29 Disulfiram ND ND ND ND ND ND ND Eplerenone >25.0 0.141 (13) >3.53 NR NR NR 0.0166 Erythromycin 16.9 0.328 (9) 5.06 27.1 (19.7) 8.13 0.0141 (0.0044) 1.73 Imatinib 22.5 1.00 (16) 22.5 29.4 (8.1) 29.4 0.0202 (0.0014) 0.687 Midostaurin >25.0 0.005 (43) >0.120 0.574 (0.165) 0.00276 0.00566 (0.00041) 2050 Nelfinavir 0.496 1.70 (12) 0.842 NR NR NR 6.24 Nitrendipine ND ND ND ND ND ND ND Panobinostat >25.0 0.600 (11) >15.0 26.0 (7.2) 15.6 0.00446 (0.00038) 0.286 Paroxetine 14.3 0.600 (14) 8.55 NR NR NR 0.113 Propiverine 7.50 0.500 (15) 3.75 1.38 (0.62) 0.690 0.0196 (0.0040) 28.4 Propranolol ND ND ND ND ND ND ND Simvastatin ND ND ND ND ND ND ND Tabimorelin 2.85 0.200 (18) 0.569 7.57 (2.62) 1.51 0.0148 (0.0013) 9.78 Tadalafil 12.9 0.600 (5) 7.71 4.26 (1.44) 2.56 0.028 (0.002) 11.0 Telaprevir 0.273 0.450 (17) 0.123 2.24 (0.95) 1.01 0.0112 (0.0011) 11.1 Terfenadine 2.17 1.40 3.04 NR NR NR 0.426 Verapamil 13.4 0.310 (20) 4.14 0.661 (0.143) 0.205 0.0172 (0.0010) 83.9 %CV, percent coefficient of variation; ND, not determined since no TDI was detected in a single concentration screen at 30 µM; NR, not reported see data analysis section for the estimation of kinact/KI,u.
↵aCalculated as measured IC50/2.
↵bCalculated from Kp (n=3) and fu,liver reported in supplemental tables.
↵cTotal value was reported since Kp,uu was not determined.
- TABLE 4
Numerical accuracy of DDI predictions determined from human liver microsomes and human hepatocytes using mechanistic static models
Model 1 Model 2 Model 3 Model 4 Relevant [I]g entrance entrance exit exit Relevant [I]h entrance entrance exit exit Fixed Input Parameters Fa 1 CYP3A kdeg,g 0.00050 min−1 CYP3A kdeg,h 0.00032 min−1 Qg 300 ml/min 300 ml/min 1213 ml/min 1213 ml/min Qh 1617 ml/min 1617 ml/min NA NA Varied Input Parameters ka 0.1 min−1 custom custom custom [I]g Total Enterocytea Free Enterocyteb Cmax,portal,uc Cavg,portal,ud [I]h Cmax,hepatic inlet,ue Cmax,hepatic inlet,ue Cmax,systemic,u Cavg,systemic,u fu,gut 1 fu,plasma fu,plasma fu,plasma Performance Human Liver Microsomes Bias (CI90%) 6.3 (4.8–8.1) 5.0 (3.8–6.5) 2.7 (2.2–3.4) 1.8 (1.5–2.3) GMFE (CI90%) 6.3 (4.8–8.1) 5.1 (3.9–6.6) 2.8 (2.3–3.5) 2.0 (1.6–2.4) RMSFE 7.38 6.09 3.37 2.42 % Within 2-fold 12 12 36 56 % Within 3-fold 16 28 48 80 % Outside 10-fold 24 16 4 0 Performance Human Hepatocytes Bias (CI90%) 3.8 (2.9–4.9) 2.7 (2.0–3.4) 1.6 (1.2–2.1) 1.1 (0.88–1.4) GMFE (CI90%) 3.8 (3.0–4.9) 2.7 (2.1–3.5) 2.0 (1.6–2.5) 1.7 (1.4–2.0) RMSFE 4.70 3.49 2.52 2.04 % Within 2-fold 24 44 56 68 % Within 3-fold 36 60 76 84 % Outside 10-fold 12 4 0 0 CI90%, 90% confidence interval; Cmax,systemic,u, unbound maximum systemic concentration; fu,gut, intestinal free fraction; kdeg,g, intestinal degradation rate; kdeg,h, hepatic degradation rate; NA, not applicable; Qg, intestinal blood flow; Qh, liver blood flow.
aAs calculated per eq. 7a.
bAs calculated per eq. 7a corrected for free fraction in plasma.
cAs calculated per eq. 7b.
dAs calculated per eq. 7c.
eAs calculated per eq. 6.
DDI Cutoff Matrix Model N Sensitivity Specificity PPV NPV PPE NPE % % % % % % Clinical ≥ 1.25-fold and prediction ≥ 1.25-fold Human liver microsomes 1 25 100 8 54 100 46 0 2 25 100 17 57 100 43 0 3 25 100 25 59 100 41 0 4 25 100 67 76 100 24 0 Human hepatocytes 1 25 100 33 62 100 38 0 2 25 100 33 62 100 38 0 3 25 100 58 72 100 28 0 4 25 92 67 75 89 25 11 Clinical ≥ 2-fold and prediction ≥ 2-fold Human liver microsomes 1 25 100 13 43 100 57 0 2 25 100 13 43 100 57 0 3 25 100 33 50 100 50 0 4 25 100 67 67 100 33 0 Human hepatocytes 1 25 100 27 48 100 52 0 2 25 100 40 53 100 47 0 3 25 90 67 64 91 36 9 4 25 70 80 70 80 30 20 Performance Human Liver Microsomes Human Hepatocytes Bias (CI90%) 1.6 (1.3–1.9) 1.1 (0.85–1.3) GMFE (CI90%) 1.7 (1.5–2.0) 1.6 (1.4–1.8) RMSFE 2.02 1.88 % Within 2-fold 64 68 % Within 3-fold 88 88 % Outside 10-fold 0 0 DDI Cutoff Matrix N Sensitivity Specificity PPV NPV PPE NPE % % % % % % Clinical ≥ 1.25-fold and prediction ≥ 1.25-fold Human liver microsomes 25 100 67 76 100 24 0 Human hepatocytes 25 85 83 85 83 15 17 Clinical ≥ 2-fold and prediction ≥ 2-fold Human liver microsomes 25 100 80 77 100 23 0 Human hepatocytes 25 70 80 70 80 30 20
Data Supplement
- Supplemental Tables -
Supplemental Tables 1-38.
Supplemental references.
- Supplemental Figures -
Supplemental Figures 1-23.
- Supplemental Tables -
