Supplemental Data

DMD #48819

Supplemental Data

Title: Application of Hybrid Approach Based on Empirical and Physiological Concept for

Predicting Pharmacokinetics in Humans

-Usefulness of Exponent on Prospective Evaluation of Predictability-

Authors: Hiroyuki Sayama, Hiroshi Komura, Motohiro Kogayu

Journal Title: Drug Metabolism and Disposition

DMD #48819

Supplemental Table 1 In vitro and in vivo data for allometric scaling of CL and Vss

fup RB in vitro CLint (mL/min/kg) in vivo CL (mL/min/kg) in vivo Vss (mL/kg) Refference Human Human Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Acivicin ------580 500 600 -- 650 930 63 Alfentanil ------800 953 -- 1069 975 -- 8 Amiodarone ------66000 4600 5110 -- 72300 -- 23 Amlodipine ------21000 25000 -- -- 32000 27000 101 Amphotericin B ------4011 5025 -- 1855 2300 3121 85 Amsacrine ------1560 2800 -- 1700 4500 7420 80 Antipyrine 1 1 0.28 3.95 -- 4.07 1.58 -- 0.62 a 8.18 a -- 7.32 a 3.53 a -- 584 a 738 a -- 903 a 657 a 720 5, 6, 12, 52, 76, 91, 118 Biperiden ------6200 9500 3600 19300 14000 -- 23, 70 Bosentan -- -- 0.68 0.87 -- 15.89 5.71 7.91 2.00 1.3 -- 72 38.1 31.43 ------49, 52 Caffeine 0.96 1 0.40 0.83 -- 1.18 2.55 -- 1.32 a 1.83 a -- 5.03 a 5.02 a -- 614 a 887 a 830 508 a 763 a 760 9, 10, 11, 17, 52, 81, 98 Cefazolin ------107 271 128 142 225 192 89 Cefmetazole ------143 235 138 220 490 368 89 Cefoperazone ------144 277 126 237 287 309 89 Cefotetan ------133 249 167 237 250 241 89 Cefpiramide ------111 454 100 109 264 660 89 Ceftizoxime ------200 239 a 268 a -- 392 a 653 a 67, 73 Chlordiazepoxide ------250 2540 -- -- 1454 -- 73, 86, 102 Chlorpheniramine ------3170 4050 -- 10100 -- -- 90 Chlorpromazine ------11200 18600 8000 -- 29100 -- 23, 90 Ciprofloxacin ------2100 4014 a 1800 3093 a 4600 -- 1, 2, 73, 95 Cyclosporine ------1450 1650 -- 3160 4540 2733 a 3, 27, 66, 88, 110 Diazepam 0.032 0.58 2.16 121.2 -- -- 92.23 -- 0.5 a 21.4 a -- -- 84.22 a -- 1085 a 7136 a -- 5500 4715 a -- 43, 93 Diclofenac ------59 a 189 a 170 57 370 -- 64, 84, 103, 107, 117 a Recalculated from plasma concentration-time profiles reported in the reference articles.

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Supplemental Table 1 Continued

fup RB in vitro CLint (mL/min/kg) in vivo CL (mL/min/kg) in vivo Vss (mL/kg) Refference Human Human Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Didanosine ------810 950 920 -- 990 900 41 Diltiazem 0.2 1.03 5.86 10.66 -- -- 191.49 -- 13.02 a 33.33 a -- -- 89.23 a -- 3110 a 3581 a 3500 -- 3400 a -- 23, 33, 54, 69, 86, 93 Dofetilide ------2800 4000 -- -- 3100 6300 97 Enprofylline ------510 638 -- 206 342 452 108 Epiroprim 0.11 1.1 1.85 2.76 8.45 -- 45.24 38.21 3.57 a 10.82 a 24.82 a -- 42.30 a 151.48 a 2501 a 8006 a 3151 a -- 4122 a 8356 a 60 Erythromycin ------886 2700 -- 6875 8400 4500 18 Ethosuximide ------630 590 800 960 700 2000 5, 21, 79 Felodipine 0.004 23.13 56.06 -- -- 127.37 -- 8.9 a 20.73 a -- -- 90.42 a -- 3262 a 2559 a -- -- 9006 a -- 4, 20, 93, 109 Fentanyl ------5207 10533 -- -- 4574 -- 8, 86 Fexofenadine ------771 -- 302 -- 4254 -- 37, 47, 75 Flindokalner ------2350 3200 5400 -- 3400 -- 23 Fluconazole ------710 700 -- 880 800 1100 39 Flunitrazepam ------4580 13000 -- -- 3810 -- 86, 102 Fluvastatin ------420 700 3700 290 7300 1000 56, 104, 105, 106 Garenoxacin ------1000 1300 1000 -- 900 -- 23 Gentamicin ------330 320 -- 338 a 398 a -- 73, 87, 99, 115 Haloperidol ------18000 37000 6600 -- 10400 -- 23 Interferon-alpha A ------449 190 190 130 261 233 48 Ketamine ------2700 4526 -- -- 3929 -- 8 Lamifiban ------290 750 290 -- 240 -- 50 Lamivudine ------1300 870 1160 -- 2700 -- 41 Lidocaine ------1080 -- 706 -- 3110 -- 90, 94 Lorazepam -- -- 0.93 71.46 -- -- 16.69 -- 1.1 26.1 -- -- 27.2 ------93 a Recalculated from plasma concentration-time profiles reported in the reference articles.

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Supplemental Table 1 Continued

fup RB in vitro CLint (mL/min/kg) in vivo CL (mL/min/kg) in vivo Vss (mL/kg) Refference Human Human Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Metazosin ------426 -- -- 847 5955 7100 46 Methadone ------3800 7600 8200 -- 7580 -- 23 Methohexitone ------4664 1815 -- 1320 3871 -- 8 Methotrexate ------308 377 -- 200 1095 a 2194 13, 14, 28, 36, 59 Mibefradil -- -- 2.84 24.48 -- 59.13 23.72 -- 7 36 -- 64 94 ------52 Midazolam 0.019 0.55 28.68 130.28 -- 73.92 483.12 -- 4.4 a 48.95 a -- 14.23 a 59.62 a -- 713 a 1582 a 3350 734 a 1648 a 2000 26, 30, 52, 72, 74, 81 Mifepristone ------300 10500 32500 -- 4300 -- 23 Mofarotene -- -- 6.17 3.95 -- -- 10.1 7.25 11 5.8 -- -- 16 27 ------52 Moxalactam ------138 197 162 234 276 241 89 Moxifloxacin ------2000 2700 4900 -- 3600 3700 96 Naloxone -- -- 51.5 126.73 -- -- 239.8 -- 25 42.5 -- -- 48.8 ------93 Napsagatran ------343 690 263 986 615 -- 53 Nicardipine 0.068 0.71 22.51 63.17 -- -- 118.58 -- 7.68 a 38.65 a -- -- 29.77 a -- 489 a 797 a 1375 a -- 808 a -- 31, 71, 86, 93 Nifedipine ------780 1150 500 -- 127 -- 23 Nilvadipine -- -- 41.02 43.03 -- -- 130.44 -- 20 15.3 -- -- 94 ------93 Nitrendipine 0.02 -- 37.01 31.98 -- -- 105.41 -- 19.23 a 17.17 a -- -- 11.28 a -- 5731 a 1543 a -- 377 a -- 45, 65, 93 Ofloxacin ------1780 1150 1600 -- 1660 -- 23 Oleandomycin ------771 1600 -- -- 6800 5500 18 Oxazepam 0.043 -- 1.23 4.74 -- -- 5.71 -- 1.58 a 4.33 a -- -- 20.22 a -- 861 a 1418 a -- -- 1258 a -- 16, 86, 93, 100, 112 Pentobarbital ------990 -- -- 1300 1640 -- 38, 91 Phencyclidine ------6200 17000 -- 23200 9000 5 Prednisolone ------860 -- -- 1370 1370 -- 24, 38, 73 Propafenone 0.024 0.7 5.52 7.80 -- -- 9.83 14.16 14.63 a 28.7 a -- -- 34.67 a 142.37 a 3492 a 2748 a -- 4500 1919 a 3130 a 34, 44, 82, 83, 86 a Recalculated from plasma concentration-time profiles reported in the reference articles.

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Supplemental Table 1 Continued

fup RB in vitro CLint (mL/min/kg) in vivo CL (mL/min/kg) in vivo Vss (mL/kg) Refference Human Human Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Human Dog Monkey Rabbit Rat Mouse Propranolol 0.068 0.81 12.95 75.01 -- -- 223.99 10.15 a 40.9 a -- -- 96.8 a -- 2421 a 1544 a 5308 a -- 4720 a -- 7, 22, 29, 52, 91 Quinidine ------3500 -- 427 5030 5800 5840 40, 90, 114 Ranitidine ------1200 1722 a -- -- 216 a -- 19, 35, 73 Recainam ------1400 1200 3800 3600 3200 -- 92 Remoxipride ------700 1600 1100 -- 4500 3200 23, 116 Sematilide ------740 1400 -- 1813 2167 -- 32 Semaxanib ------980 1400 1450 -- 1600 -- 23 Sildenafil ------1200 5200 -- -- 1100 1000 113 Stavudine ------530 -- 920 -- 700 760 41 Sumatriptan ------1635 2027 -- 4143 2642 -- 15 Susalimod ------120 190 80 170 1200 310 77 Tamsulosin ------205 1778 -- 2711 2857 -- 111 Theophylline 0.51 0.83 0.34 0.59 -- 0.89 0.79 -- 0.82 a 1.52 a -- 3.18 a 1.9 a -- 579 a 710 a -- 923 a 857 a 840 5, 25, 42, 52, 57, 86, 119 Thiopentone ------1757 1499 -- 613 943 -- 8 Tolcapone 0.001 0.6 3.7 5.53 -- 16.26 11.42 -- 1.43 a 1.45 a -- 10.82 a 5.7 a -- 124 a 220 a -- 153 a 98 a -- 51 Tolterodine ------1800 1500 -- -- 23000 16000 78 Triazolam ------1260 1400 -- -- 2240 -- 86, 102 Valproic Acid ------150 306 -- -- 657 331 58 Verapamil 0.082 0.84 4.61 8.36 -- -- 5.19 -- 11.78 a 23.43 a -- -- 34.22 a -- 3329 a 3582 a -- -- 3016 a -- 55, 61, 62, 83, 86 Vinorelbine ------75600 49600 11400 -- 24400 -- 23 Warfarin ------122 148 143 -- 113 -- 68 Zalcitabine ------540 -- 870 -- 1540 590 41 Zidovudine ------1400 1000 1080 -- 1610 730 41 a Recalculated from plasma concentration-time profiles reported in the reference articles.

DMD #48819

Supplemental Table 2 Physiological Parameters used in the PBPK model Fraction Tissue Volume Tissue Concentration Tissue to Plasma Ratio Tissue Volume Blood Flow Tissue Neutral Neutral Extracellular Intracellular of Acidic Phospholipids (mL/kg) (mL/min/kg) Albumin Lipoprotein Lipid Phospholipid Water Water (mg/g) Venous blood 51.4 ------Arterial blood 25.7 ------Lung 7.6 68.3 0.022 0.0128 0.336 0.446 3.91 0.212 0.168 Adipose 233.8 3.7 0.853 0.0016 0.135 0.017 0.4 0.049 0.068 Bone 105.1 3.7 0.017 0.0017 0.1 0.346 0.67 0.1 0.05 Brain 20 8.9 0.039 0.0015 0.162 0.62 0.4 0.048 0.041 Heart 4.7 3 0.014 0.0111 0.32 0.456 2.25 0.157 0.16 Muscle 400 12.6 0.01 0.0072 0.118 0.63 1.53 0.064 0.059 Kidney 4.4 14.1 0.012 0.0242 0.273 0.483 5.03 0.13 0.137 Liver 25.7 4.5 0.014 0.024 0.161 0.573 4.56 0.086 0.161 Spleen 2.6 1.1 0.0077 0.0113 0.207 0.579 3.18 0.097 0.207 Small intestine 17.1 13 0.038 0.0125 0.282 0.475 2.41 0.158 0.141 Skin 37.1 3.7 0.06 0.0044 0.382 0.291 1.32 0.277 0.096

DMD #48819

20 AC5 Mean 2.09 ± 2.37 Mean 7.89 ± 7.30 4 15 Range -3.65 to 8.95 Range 0.50 to 25.0 3 10 2 Frequency 5 1

0 0 -3 -1 1 3 5 7 9 1 5 9 13 17 21 25

20 BD5 Mean 2.99 ± 1.73 Mean 6.64 ± 6.04 4 15 Range -0.04 to 5.30 Range 0.50 to 19.2 3 10 2 Frequency 5 1

0 0 -3 -1 1 3 5 7 9 1 5 9 13 17 21 25 clogP Observed Human CL (mL/min/kg)

Supplemental Figure 1

A and B, Distribution of clogP on the dataset of all compounds (A) and 15 model compounds used for the prediction of plasma concentration-time profiles in humans (B). C and D,

Distribution of observed human CL on the dataset of all compounds (C) and 15 model compounds used for the prediction of plasma concentration-time profiles in humans (D).

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Supplemental Figure 2

Scheme of the generic PBPK model used for simulation of plasma concentration profiles. For more details, refer to Materials and Methods.

DMD #48819

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