Short Title: Study the Impact of Excipient on Absorption Using PBPK Modeling

Using physiologically based pharmacokinetic (PBPK) modeling to evaluate the risk of pharmaceutical excipients on oral drug absorption: sensitivity analyses

Short Title: Study the impact of excipient on absorption using PBPK modeling

Authors: Edwin Chiu Yuen Chow1,*, Arjang Talattof1,*, Eleftheria Tsakalozou1,*, Jianghong Fan1,*, Liang Zhao1,*, Xinyuan Zhang1,*

1 Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, MD, USA

* Disclaimer: The views expressed in this article are those of the authors and not necessarily those of the Food and Drug Administration (FDA).

Correspondence to: Xinyuan Zhang, 10903 New Hampshire Ave., Bldg. 75, Room 4612, Silver Spring, MD 20993, Phone: 240-402-7971, Email:

Supplementary Table 1: Pharmacokinetic information on Evaluated BCS Class Drug Products

Parameters / Metoprolol / Midazolam / Propranolol / Theophylline / Digoxin / Rifampicin / Risperidone / Rosuvastatin / Talinolol / Atenolol / Cefadroxil / Pravastatin / Ranitidine
Regional Intestinal Permeability
Intestinal Effective Permeability *10-4 (cm/sec) / 1.5 / 2.91 / 2.91 / 5 / 0.8 / 1.95 / 0.29 / 0.2 / 0.35 / 1.276 / 0.27
Stomach / 0* / 0 / 0 / 0 / 0.5 / 0** / 0** / 0.8549 / 0** / 0** / 0 / 0 / 0**
Duodenum / 1.235* / 2.741 / 2.727 / 2.886 / 4.67 / 2.764** / 2.750** / 0.8549 / 2.742** / 2.668** / 2.798 / 0.647 / 2.633**
Jejunum1 / 1.321* / 2.697 / 2.678 / 2.862 / 4.67 / 2.33** / 2.724** / 0.8549 / 2.718** / 2.655** / 2.753 / 1.276 / 2.634**
Jejunum2 / 1.485* / 2.69 / 2.675 / 2.817 / 4.67 / 2.724** / 2.721** / 0.8549 / 2.718** / 2.628** / 2.73 / 0.893 / 2.621**
Ileum1 / 1.695* / 2.653 / 2.64 / 2.806 / 4.67 / 2.03** / 2.707** / 0.8549 / 2.710** / 2.593** / 2.697 / 0.401 / 2.6**
Ileum2 / 2.006* / 2.617 / 2.621 / 2.727 / 4.67 / 2.663** / 2.680** / 0.8549 / 2.692** / 2.576** / 2.641 / 0.401 / 2.599**
Ileum3 / 2.462* / 2.553 / 2.589 / 2.675 / 4.67 / 2.608** / 2.655** / 0.8549 / 2.687** / 2.532** / 2.571 / 0.394 / 2.57**
Ileum4 / N/A / N/A / N/A / N/A / 4.67 / 0.8549 / NA / 0.379 / NA
Caecum / 0.066* / 1.943 / 0.352 / 0.13 / 0.992** / 0.504** / 0.256** / 0.00907** / 0.013 / NA / 0.035**
Asc Colon / 0.101* / 4.161 / 0.823 / 0.252 / 0.1 / 2.532** / 1.477** / 0.8549 / 0.739** / 0.019** / 0.024 / 0.259 / 0.102**
Volume of distribution
# of Compartmental or Full PBPK / 2 / Fulla / 2 / 1 / Fullb / Fulla / Fulla / Fullb / 3 / 1 / 1 / Fullb / 1
Vc (L/kg) / 0.07338 / 2.91 / 0.5 / 1.2124 / 0.95 / 0.29 / 1.3
k12 (hr-1) / 6.2497 / 0.291 / 1.3667 / 0 / 0
k21 (hr-1) / 0.52196 / 0.641 / 0.97801 / 0 / 0
V2 (L/kg) / 0.87862 / 1.3211 / 1.6942 / 0 / 0
k13 (hr-1) / 0.51615 / 0 / 0
k31 (hr-1) / 0.14343 / 0 / 0
V3 (L/kg) / 4.363 / 0 / 0
Clearances
Total CL (L/h) / 0.75215 / 3.36 / 26.517 / 8.4 / 0.13 / 20 / 43.68
CLrenal (L/h) / 0 / 0 / 0.5278 / 16 / 1.184 / 0.758 / 17 / 0 / 0.13 / 27.218 / 0

NA denotes not available

aKp prediction using perfusion limited tissue model using Lukacova (Rogers-Single) method and permeability limited tissue model using Poulin&Theil-Extracellular method in Gastroplus

bKp prediction using Rodgers et al. method in Simcyp

*Coefficient in Absorption Scale Factor Scaling 0.18148 (C1), 1.0944 (C2), 0.0734 (C3), 0.31836 (C4)

**Coefficient in Absorption Scale Factor Scaling 0.06944 (C1), 0.43028 (C2), 0.12147 (C3), 0.46632 (C4)

Supplementary Table 2: Intestinal and Liver Enzyme Substrate Information on Evaluated BCS Class Drug Products

Parameters / Metoprolol / Midazolam / Digoxin / Rifampicin / Risperidone / Rosuvastatin
Intestinal Enzyme / CYP2D6 / CYP3A4 / Hepatic enzyme / CYP3A4
Vmax (mg/s) / 0.081 / 0.305 / 0.25 / 0.151
Km (mg/L) / 9.625 / 0.977 / 0.4 / 3.025
Intestinal Enzyme Vmax Scale Factor / 1 / 1 / 1 / 1
Intestinal Enzyme Distribution
Stomach / 0 / 0 / 0 / 0
Duodenum / 0.000206 / 0.0029 / 0.0029 / 0.0029
Jejunum1 / 0.000412 / 0.00326 / 0.00326 / 0.00326
Jejunum2 / 0.000456 / 0.00326 / 0.00326 / 0.00326
Ileum1 / 0.00069 / 0.00103 / 0.00103 / 0.00103
Ileum2 / 0.000719 / 0.00103 / 0.00103 / 0.00103
Ileum3 / 0.000416 / 0.00103 / 0.00103 / 0.00103
Caecum / 0 / 0.00031 / 0.00031 / 0.00031
Asc Colon / 0 / 0.00031 / 0.00031 / 0.00031
Liver Enzyme / CYP2D6 / CYP3A4 / Hepatic enzyme / CYP3A4
Vmax (mg/s) / 0.081 / 0.000884 / 0.25 / 0.000484
Km (mg/L) / 9.625 / 0.977 / 0.4 / 3.025
Liver Enzyme Vmax Scale Factor / 1 / 1 / 1 / 1
Liver CLint / 0.37 ul/min/106 from hepatocytes / 17 uL/min/mg protein from HLM

Supplementary Table 3: Intestinal and Liver Transporter Substrate Information on Evaluated BCS Class Drug Products

Parameters / Digoxin / Rosuvastatin / Talinolol / Cefadroxil / Pravastatin
Intestinal Transporter / BCRP / OATP1A2 / P-gp / PEPT1 / MRP2
CLint,T, in vitro transporter-mediated intrinsic clearance (µl/min) / 35 / 1.2
Jmax (pmol/min/million cells) / 434
Km (uM) / 177
Intestinal Transporter Relative Activity Factor / 2 / 1 / 0.18
Vmax (mg/s) / 0.15 / 0.356 / 0.037
Km (mg/L) / 727 / 37.4 / 399.7
Intestinal Transporter Scaling Factor or Relative Activity Factor / 1
Intestinal Transporter Vmax Scaling Factor / 3.1007 / 0.4173 / 1
Intestinal Transporter Km Scaling Factor / 1 / 0.0197 / 1
Intestinal Transporter Distribution
Stomach / 0 / 0 / 0 / 0 / 0
Duodenum / 0.47 / 0.07 / 0.538 / 9.007 / 1.41
Jejunum1 / 1 / 0.07 / 0.645 / 1.639 / 1
Jejunum2 / 1 / 0.07 / 0.723 / 1.633 / 1
Ileum1 / 0.59 / 1 / 0.77 / 1.086 / 0.6
Ileum2 / 0.59 / 1 / 0.838 / 1.097 / 0.6
Ileum3 / 0.59 / 1 / 0.908 / 1.096 / 0.6
Ileum4 / 0.59 / NA / 0.6
Caecum / 0.13 / 1 / 0
Asc Colon / 0.13 / 0.17 / 1 / 0 / 0.02
Liver Transporter / BCRP / OATP1B1 / OATP1B3 / OCT1 / MRP2 / OATP1B1 / OATP1B3
CLPD, passive diffusion clearance (ml/min/million hepatocytes) / 0.1 / 0.0025 / 0.000109
CLint, T, in vitro transporter-mediated intrinsic clearance (µl/min/million cells) / 1.23 / 109 / 36 / 78 / 1.2 / 14.057 / 1.343
Jmax (pmol/min/million cells) / 434
Km (µM) / 177
Liver Transporter Scaling Factor or Relative Activity Factor / 1.5 / 1 / 1 / 1 / 1 / 0.18 / 1 / 1

Supplementary Figure 1: Changes in solubility on (A, B, and C) systemic bioavailability (F), (D, E, and F) fractional absorbed (fa), (G, H, and I) intestinal availability (fg), (J, K, and L) fafg, and (M, N, and O) time to reach maximum plasma/blood concentration (tmax) for BCS class 1, 2, and 3 drugs

Supplementary Figure 2:Changes in passive permeability on (A, B, and C) systemic bioavailability (F), (D, E, and F) fractional absorbed (fa), (G, H, and I) intestinal availability (fg), (J, K, and L) fafg, and (M, N, and O) time to reach maximum plasma/blood concentration (tmax) for BCS class 1, 2, and 3 drugs

Supplementary Figure 3: Changes in enzymatic activity on (A and B) systemic bioavailability (F), (C and D) fractional absorbed (fa), (E and F) intestinal availability (fg), (G and H) fafg, and (I and J) time to reach maximum plasma/blood concentration (tmax) for BCS class 1 and 2 drugs

Supplementary Figure 4: Changes in influx transport on (A and B) systemic bioavailability (F), (C and D) fractional absorbed (fa), (E and F) intestinal availability (fg), (G and H) fafg, and (I and J) time to reach maximum plasma/blood concentration (tmax) for BCS class 2 and 3 drugs

Supplementary Figure 5: Changes in efflux transport on (A and B) systemic bioavailability (F), (C and D) fractional absorbed (fa), (E and F) intestinal availability (fg), (G and H) fafg, and (I and J) time to reach maximum plasma/blood concentration (tmax) for BCS class 2 and 3 drugs