Modeling Dynamic Gastrointestinal Fluid Transit as a Basis for Dissolution and Absorption

Duxin Sun PhD

William I Higuchi Collegiate Professor

Department of Pharmaceutical Sciences

Pharmacokinetics core

Interdepartmental Program in Medicinal Chemistry

Chemical Biology Program

Comprehensive Cancer Center

University of Michigan

Ann Arbor MI 48109

Oral Absorption is a Highly Complex Process Where GI Fluid Volume can Impact Oral Absorption

Compartmental Approach has Demonstrated Some Success in Predicting Oral Absorption

Question is there in vivo consideration of GI fluid volume

Three Compartment Models ComparedStatic Volume per Compartment Assumption

volume (mL) transit time (min) pH

GI compartment SCb G+ GS SC G+ GS SC G+ GS

1 53 50 47 24 6 15 15 13 13

2 35 48 42 92 16 16 64 60 60

3 24 175 150 35 57 56 65 62 62

4 24 140 120 35 46 44 66 64 64

5 14 109 94 30 35 35 68 66 66

6 14 79 71 30 26 25 70 69 69

7 14 56 50 30 19 17 71 74 74

8 14 53 30 270 73 64

9 13 57 720 810 65 68

Sjoumlgren et al In Silico Modeling of Gastrointestinal Drug Absorption Predictive Performance of Three Physiologically Based Absorption ModelsMol Pharmaceutics 2016 13 (6) pp 1763ndash1778

Physiological Parameters for the Evaluated Intestinal Absorption Models Included

in Simcyp (SC) GastroPlus (G+) and GI-Sim (GS)

4

Oral Absorption is a Highly Complex Process Where GI Fluid Volume can Impact Oral Absorption

Compartmental Approach has Demonstrated Some Success in Predicting Oral Absorption

Question is there in vivo consideration of GI fluid volume

Three Compartment Models ComparedStatic Volume per Compartment Assumption

volume (mL) transit time (min) pH

GI compartment SCb G+ GS SC G+ GS SC G+ GS

1 53 50 47 24 6 15 15 13 13

2 35 48 42 92 16 16 64 60 60

3 24 175 150 35 57 56 65 62 62

4 24 140 120 35 46 44 66 64 64

5 14 109 94 30 35 35 68 66 66

6 14 79 71 30 26 25 70 69 69

7 14 56 50 30 19 17 71 74 74

8 14 53 30 270 73 64

9 13 57 720 810 65 68

Sjoumlgren et al In Silico Modeling of Gastrointestinal Drug Absorption Predictive Performance of Three Physiologically Based Absorption ModelsMol Pharmaceutics 2016 13 (6) pp 1763ndash1778

Physiological Parameters for the Evaluated Intestinal Absorption Models Included

in Simcyp (SC) GastroPlus (G+) and GI-Sim (GS)

4

Compartmental Approach has Demonstrated Some Success in Predicting Oral Absorption

Question is there in vivo consideration of GI fluid volume

Three Compartment Models ComparedStatic Volume per Compartment Assumption

volume (mL) transit time (min) pH

GI compartment SCb G+ GS SC G+ GS SC G+ GS

1 53 50 47 24 6 15 15 13 13

2 35 48 42 92 16 16 64 60 60

3 24 175 150 35 57 56 65 62 62

4 24 140 120 35 46 44 66 64 64

5 14 109 94 30 35 35 68 66 66

6 14 79 71 30 26 25 70 69 69

7 14 56 50 30 19 17 71 74 74

8 14 53 30 270 73 64

9 13 57 720 810 65 68

Sjoumlgren et al In Silico Modeling of Gastrointestinal Drug Absorption Predictive Performance of Three Physiologically Based Absorption ModelsMol Pharmaceutics 2016 13 (6) pp 1763ndash1778

Physiological Parameters for the Evaluated Intestinal Absorption Models Included

in Simcyp (SC) GastroPlus (G+) and GI-Sim (GS)

4

Three Compartment Models ComparedStatic Volume per Compartment Assumption

volume (mL) transit time (min) pH

GI compartment SCb G+ GS SC G+ GS SC G+ GS

1 53 50 47 24 6 15 15 13 13

2 35 48 42 92 16 16 64 60 60

3 24 175 150 35 57 56 65 62 62

4 24 140 120 35 46 44 66 64 64

5 14 109 94 30 35 35 68 66 66

6 14 79 71 30 26 25 70 69 69

7 14 56 50 30 19 17 71 74 74

8 14 53 30 270 73 64

9 13 57 720 810 65 68

Sjoumlgren et al In Silico Modeling of Gastrointestinal Drug Absorption Predictive Performance of Three Physiologically Based Absorption ModelsMol Pharmaceutics 2016 13 (6) pp 1763ndash1778

Physiological Parameters for the Evaluated Intestinal Absorption Models Included

in Simcyp (SC) GastroPlus (G+) and GI-Sim (GS)

4

Static Volume Assumption Leads Primarily to Mass Driven Absorptionbull Primary terms for calculating absorption

bull ACAT

Absorption (119889119898

119889119905) = 119896 119894 119886119881(119894)(119862 119894 119871 minus 119862 119894 119864)

bull ADAM 119889119862119890119899119905119899119889119905

=1

119881119890119899119905119899(119860119889119894119904119904119899119896119886119899)

bull Rate of absorption differs between compartments

bull Use of constant volumes leads to mass driven absorption calculations in each compartment

This does not always characterize the real in vivo volume and its dynamic change that influences absorption in the GI tract

Dynamic Fluid Model Reflects in vivo GI Volume Changes

asympMn(t)

Cn(t)

Absorption

Dissolution

Solid

V(n)

Dissolution Mn(t)

Estimation Vn(t)

Solid Dissolution Mn(t)

Absorption

AbsorptionDissolution

Estimation

New Dynamic Volume Approach

Traditional Approach

Absorption

Dynamic Fluid Compartment Absorption and Transport Model

Stomach Small Intestine

VI30

MI30

VIn

MIn

VI3

MI3

VI2

MI2

VI1

MI1

VS

MSDrug

Fluid

Systemic Circulation

SecretionAbsorption

Tra

nsi

t to

Co

lon

Defining Attributesbull Thirty small intestine compartments in seriesbull Forward and retrograde transitbull Net secretion in the stomachbull Secretion and absorption in duodenumbull Net absorption throughout the rest of small intestine

Poster 09T0200 Alex Yu

Impact of Unknown Volume in GI Tract

Previously no available data of in vivo GI volumeGenerates uncertainty for basis in in vitro drug dissolution conditions and in vivo drug dissolution prediction

bull MRI study in human has provided total volume of stomach small intestine and colon bull it did not provide volume of each segment of GI tractbull It did not provide dynamic volume change of each segment

Dynamic change of GI fluid volume in each segment of GI tract is required to predict in vivo dissolution and concentration driven absorption

There is no method to measure water secretion and absorption in the GI tract which drives additional volume change

Building a dynamic model needs to be based on extensive verification with clinical reference data

Measurement of Gastrointestinal (GI) Fluid Volume using MRI

Mol Pharm 2014 Sep 211(9)3039-47 doi 101021mp500210c Epub 2014 Aug 19Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted stateMudie DM1 Murray K Hoad CL Pritchard SE Garnett MC Amidon GL Gowland PA Spiller RC Amidon GE Marciani L

Dynamic Fluid Model Reflects in vivo GI Volume Changes

asympMn(t)

Cn(t)

Absorption

Dissolution

Solid

V(n)

Dissolution Mn(t)

Estimation Vn(t)

Solid Dissolution Mn(t)

Absorption

AbsorptionDissolution

Estimation

New Dynamic Volume Approach

Traditional Approach

Absorption

Dynamic Fluid Compartment Absorption and Transport Model

Stomach Small Intestine

VI30

MI30

VIn

MIn

VI3

MI3

VI2

MI2

VI1

MI1

VS

MSDrug

Fluid

Systemic Circulation

SecretionAbsorption

Tra

nsi

t to

Co

lon

Defining Attributesbull Thirty small intestine compartments in seriesbull Forward and retrograde transitbull Net secretion in the stomachbull Secretion and absorption in duodenumbull Net absorption throughout the rest of small intestine

Poster 09T0200 Alex Yu

Impact of Unknown Volume in GI Tract

Previously no available data of in vivo GI volumeGenerates uncertainty for basis in in vitro drug dissolution conditions and in vivo drug dissolution prediction

bull MRI study in human has provided total volume of stomach small intestine and colon bull it did not provide volume of each segment of GI tractbull It did not provide dynamic volume change of each segment

Dynamic change of GI fluid volume in each segment of GI tract is required to predict in vivo dissolution and concentration driven absorption

There is no method to measure water secretion and absorption in the GI tract which drives additional volume change

Building a dynamic model needs to be based on extensive verification with clinical reference data

Measurement of Gastrointestinal (GI) Fluid Volume using MRI

Mol Pharm 2014 Sep 211(9)3039-47 doi 101021mp500210c Epub 2014 Aug 19Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted stateMudie DM1 Murray K Hoad CL Pritchard SE Garnett MC Amidon GL Gowland PA Spiller RC Amidon GE Marciani L

Dynamic Fluid Compartment Absorption and Transport Model

Stomach Small Intestine

VI30

MI30

VIn

MIn

VI3

MI3

VI2

MI2

VI1

MI1

VS

MSDrug

Fluid

Systemic Circulation

SecretionAbsorption

Tra

nsi

t to

Co

lon

Defining Attributesbull Thirty small intestine compartments in seriesbull Forward and retrograde transitbull Net secretion in the stomachbull Secretion and absorption in duodenumbull Net absorption throughout the rest of small intestine

Poster 09T0200 Alex Yu

Impact of Unknown Volume in GI Tract

Previously no available data of in vivo GI volumeGenerates uncertainty for basis in in vitro drug dissolution conditions and in vivo drug dissolution prediction

bull MRI study in human has provided total volume of stomach small intestine and colon bull it did not provide volume of each segment of GI tractbull It did not provide dynamic volume change of each segment

Dynamic change of GI fluid volume in each segment of GI tract is required to predict in vivo dissolution and concentration driven absorption

There is no method to measure water secretion and absorption in the GI tract which drives additional volume change

Building a dynamic model needs to be based on extensive verification with clinical reference data

Measurement of Gastrointestinal (GI) Fluid Volume using MRI

Mol Pharm 2014 Sep 211(9)3039-47 doi 101021mp500210c Epub 2014 Aug 19Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted stateMudie DM1 Murray K Hoad CL Pritchard SE Garnett MC Amidon GL Gowland PA Spiller RC Amidon GE Marciani L

Impact of Unknown Volume in GI Tract

Previously no available data of in vivo GI volumeGenerates uncertainty for basis in in vitro drug dissolution conditions and in vivo drug dissolution prediction

bull MRI study in human has provided total volume of stomach small intestine and colon bull it did not provide volume of each segment of GI tractbull It did not provide dynamic volume change of each segment

Dynamic change of GI fluid volume in each segment of GI tract is required to predict in vivo dissolution and concentration driven absorption

There is no method to measure water secretion and absorption in the GI tract which drives additional volume change

Building a dynamic model needs to be based on extensive verification with clinical reference data

Measurement of Gastrointestinal (GI) Fluid Volume using MRI

Mol Pharm 2014 Sep 211(9)3039-47 doi 101021mp500210c Epub 2014 Aug 19Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted stateMudie DM1 Murray K Hoad CL Pritchard SE Garnett MC Amidon GL Gowland PA Spiller RC Amidon GE Marciani L

Measurement of Gastrointestinal (GI) Fluid Volume using MRI

Mol Pharm 2014 Sep 211(9)3039-47 doi 101021mp500210c Epub 2014 Aug 19Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted stateMudie DM1 Murray K Hoad CL Pritchard SE Garnett MC Amidon GL Gowland PA Spiller RC Amidon GE Marciani L

Stomach Fluid Transport Analysis

StomachVS

SecretionksS

EmptyingkqS

Water Intake

240mL

0

25

50

75

100

125

150

175

200

225

250

-10 0 10 20 30 40 50 60 70 80 90 100110120

Ga

str

ic liq

uid

vo

lum

e (

mL

)

Time (min)

240mL water drink studyGastric liquid volumes

n=12 (meanplusmnSEM)

AssumeZero order secretion (constant)First order emptying

Define terms based on best fit

Mol Pharm 2014 Sep 211(9)3039-47 doi 101021mp500210c Epub 2014 Aug 19Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted stateMudie DM1 Murray K Hoad CL Pritchard SE Garnett MC Amidon GL Gowland PA Spiller RC Amidon GE Marciani L

Stomach Fluid Transport Analysis

Simulation in Blue

Clinically Measured Volume using MRI in Red

Fluid Transport Analysis of Stomach and Small Intestine

StomachVS

IntestineVI

SecretionksS

EmptyingkqS

Exit to Colon

Absorptionkwa

SecretionksI

Water Intake

Two Unknowns to EstimateSecretion and Exit to Colon (dependent on transit speed)

240mL

Literature based estimationFirst order absorption

Minimal

Residual Analysis Based on Small Intestine MRT to Develop The Intestinal Fluid Transit Model

bull Surface plot indicates residual (z axis) (blue is low)

bull Overall cumulative exit is similar to MRT in small intestine as previously reported

Adv Drug Del Rev 1996 Jun 12 19(3) 359-376 doi 1010160169-409X(96)00009-9 Transport approaches to the biopharmaceutical design of oral drug delivery systems prediction of intestinal absorptionLawrence X Yu a 1 Elke Lipka b John R Crison b Gordon L Amidon

Fluid Transport Analysis of Stomach and Small Intestine

StomachVS

IntestineVI

SecretionksS

EmptyingkqS

Exit to Colon

Absorptionkwa

SecretionksI

Water Intake

Two Unknowns to EstimateSecretion and Exit to Colon (dependent on transit speed)

240mL

Literature based estimationFirst order absorption

Minimal

Residual Analysis Based on Small Intestine MRT to Develop The Intestinal Fluid Transit Model

bull Surface plot indicates residual (z axis) (blue is low)

bull Overall cumulative exit is similar to MRT in small intestine as previously reported

Adv Drug Del Rev 1996 Jun 12 19(3) 359-376 doi 1010160169-409X(96)00009-9 Transport approaches to the biopharmaceutical design of oral drug delivery systems prediction of intestinal absorptionLawrence X Yu a 1 Elke Lipka b John R Crison b Gordon L Amidon

Residual Analysis Based on Small Intestine MRT to Develop The Intestinal Fluid Transit Model

bull Surface plot indicates residual (z axis) (blue is low)

bull Overall cumulative exit is similar to MRT in small intestine as previously reported

Adv Drug Del Rev 1996 Jun 12 19(3) 359-376 doi 1010160169-409X(96)00009-9 Transport approaches to the biopharmaceutical design of oral drug delivery systems prediction of intestinal absorptionLawrence X Yu a 1 Elke Lipka b John R Crison b Gordon L Amidon

MRI Measurement and Modeling of Small Intestinal Fluid

Mol Pharm 2014 Sep 211(9)3039-47 doi 101021mp500210c Epub 2014 Aug 19Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted stateMudie DM1 Murray K Hoad CL Pritchard SE Garnett MC Amidon GL Gowland PA Spiller RC Amidon GE Marciani L

Simulation in Blue

Clinically Measured Volume using MRI in Red

MRI Measurement and Modeling of Upper and Lower Small Intestinal Fluid

bull UpperLower small intestine fluid volumes were quantified in the MRI study

Clinical Evaluation of Dynamic Fluid Transit Model by GI Intubation and Measurement of Non-absorbable Marker in the GI tract

bull Fasted healthy volunteers

bull Dose 240mL of Phenol Red (Non-absorbable marker)

bull Clinical GI Intubation Study bull Multi-lumen GI tube bull 4 aspiration ports to obtain GI samples

Multi-Lumen GI Tube

1

43

2

Measurement of Phenol Red Concentration in the GI tract and Simulation of Phenol Red Concentration based on Dynamic Volume Change

Simulation in Blue

Clinically Measured Phenol Red Concentration in the GI tract in Red

More refinement needed

Case Study Apply Dynamic Fluid Transit Model to Predict PK Profile after Oral Dosing of Mesalamine Solution

bull Human volunteers

bull Drug 125 ml Mesalamine100 mg oral solution followed by 125 ml water

bull Measure mesalamine plasma concentration for pharmacokinetic parameters analysis

bull Apply dynamic fluid transit model to simulate plasma drug profile

bull Compare with traditional CAT model to simulate plasma drug profile

Average plasma concentrations observed for 5-ASA and Ac-5-ASA when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

5-ASA Ac-5-ASA

0

5

10

15

20

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Concentr

ation (

nM

)

Drug Formulation

Pentasa

Apriso

Lialda

Solution

Individual plasma concentrations observed for 5-ASA (left) and Ac-5-ASA (right) when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Solution Pentasa

Apriso Lialda

0

5

10

15

20

25

0

10

20

30

0

5

10

15

20

0

2

4

6

0 5 10 15 20 25 0 5 10 15 20 25

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Conc

entra

tion (

nM)

5-ASA

Dynamic Fluid Models Can Better Characterize the Early Absorption Process

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Clinical Evaluation of Dynamic Fluid Transit Model by GI Intubation and Measurement of Non-absorbable Marker in the GI tract

bull Fasted healthy volunteers

bull Dose 240mL of Phenol Red (Non-absorbable marker)

bull Clinical GI Intubation Study bull Multi-lumen GI tube bull 4 aspiration ports to obtain GI samples

Multi-Lumen GI Tube

1

43

2

Measurement of Phenol Red Concentration in the GI tract and Simulation of Phenol Red Concentration based on Dynamic Volume Change

Simulation in Blue

Clinically Measured Phenol Red Concentration in the GI tract in Red

More refinement needed

Case Study Apply Dynamic Fluid Transit Model to Predict PK Profile after Oral Dosing of Mesalamine Solution

bull Human volunteers

bull Drug 125 ml Mesalamine100 mg oral solution followed by 125 ml water

bull Measure mesalamine plasma concentration for pharmacokinetic parameters analysis

bull Apply dynamic fluid transit model to simulate plasma drug profile

bull Compare with traditional CAT model to simulate plasma drug profile

Average plasma concentrations observed for 5-ASA and Ac-5-ASA when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

5-ASA Ac-5-ASA

0

5

10

15

20

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Concentr

ation (

nM

)

Drug Formulation

Pentasa

Apriso

Lialda

Solution

Individual plasma concentrations observed for 5-ASA (left) and Ac-5-ASA (right) when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Solution Pentasa

Apriso Lialda

0

5

10

15

20

25

0

10

20

30

0

5

10

15

20

0

2

4

6

0 5 10 15 20 25 0 5 10 15 20 25

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Conc

entra

tion (

nM)

5-ASA

Dynamic Fluid Models Can Better Characterize the Early Absorption Process

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Measurement of Phenol Red Concentration in the GI tract and Simulation of Phenol Red Concentration based on Dynamic Volume Change

Simulation in Blue

Clinically Measured Phenol Red Concentration in the GI tract in Red

More refinement needed

Case Study Apply Dynamic Fluid Transit Model to Predict PK Profile after Oral Dosing of Mesalamine Solution

bull Human volunteers

bull Drug 125 ml Mesalamine100 mg oral solution followed by 125 ml water

bull Measure mesalamine plasma concentration for pharmacokinetic parameters analysis

bull Apply dynamic fluid transit model to simulate plasma drug profile

bull Compare with traditional CAT model to simulate plasma drug profile

Average plasma concentrations observed for 5-ASA and Ac-5-ASA when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

5-ASA Ac-5-ASA

0

5

10

15

20

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Concentr

ation (

nM

)

Drug Formulation

Pentasa

Apriso

Lialda

Solution

Individual plasma concentrations observed for 5-ASA (left) and Ac-5-ASA (right) when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Solution Pentasa

Apriso Lialda

0

5

10

15

20

25

0

10

20

30

0

5

10

15

20

0

2

4

6

0 5 10 15 20 25 0 5 10 15 20 25

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Conc

entra

tion (

nM)

5-ASA

Dynamic Fluid Models Can Better Characterize the Early Absorption Process

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Case Study Apply Dynamic Fluid Transit Model to Predict PK Profile after Oral Dosing of Mesalamine Solution

bull Human volunteers

bull Drug 125 ml Mesalamine100 mg oral solution followed by 125 ml water

bull Measure mesalamine plasma concentration for pharmacokinetic parameters analysis

bull Apply dynamic fluid transit model to simulate plasma drug profile

bull Compare with traditional CAT model to simulate plasma drug profile

Average plasma concentrations observed for 5-ASA and Ac-5-ASA when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

5-ASA Ac-5-ASA

0

5

10

15

20

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Concentr

ation (

nM

)

Drug Formulation

Pentasa

Apriso

Lialda

Solution

Individual plasma concentrations observed for 5-ASA (left) and Ac-5-ASA (right) when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Solution Pentasa

Apriso Lialda

0

5

10

15

20

25

0

10

20

30

0

5

10

15

20

0

2

4

6

0 5 10 15 20 25 0 5 10 15 20 25

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Conc

entra

tion (

nM)

5-ASA

Dynamic Fluid Models Can Better Characterize the Early Absorption Process

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Average plasma concentrations observed for 5-ASA and Ac-5-ASA when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

5-ASA Ac-5-ASA

0

5

10

15

20

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Concentr

ation (

nM

)

Drug Formulation

Pentasa

Apriso

Lialda

Solution

Individual plasma concentrations observed for 5-ASA (left) and Ac-5-ASA (right) when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Solution Pentasa

Apriso Lialda

0

5

10

15

20

25

0

10

20

30

0

5

10

15

20

0

2

4

6

0 5 10 15 20 25 0 5 10 15 20 25

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Conc

entra

tion (

nM)

5-ASA

Dynamic Fluid Models Can Better Characterize the Early Absorption Process

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Individual plasma concentrations observed for 5-ASA (left) and Ac-5-ASA (right) when administered a dose of 100mg mesalamine solution 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Solution Pentasa

Apriso Lialda

0

5

10

15

20

25

0

10

20

30

0

5

10

15

20

0

2

4

6

0 5 10 15 20 25 0 5 10 15 20 25

0 5 10 15 20 25 0 5 10 15 20 25

Time (hr)

Conc

entra

tion (

nM)

5-ASA

Dynamic Fluid Models Can Better Characterize the Early Absorption Process

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Dynamic Fluid Models Can Better Characterize the Early Absorption Process

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject

Blue SimulationRed MRI measurement

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject

Blue SimulationRed MRI measurement

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract

bull After dosing mesalamine Solution 100mg

bull Model depicts physical transit through GIbull Left (Duodenum) to Right (Ileum)

bull Three different individuals

Low Concentration High Concentration

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals

bull Same 100mg solution dosing

bull Same pharmacokinetic parameters

bull Only dynamic volume has changed

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Summary

bull Dynamic fluid model simulates fluid transit and volume dynamics in stomach and small intestine with 30 compartments which mimic physiology relevant fluid volumes in human

bull Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing

bull Future studiesbull Refine the model to simulate concentration of non-

absorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract)

bull Add MMC into current Dynamic fluid model

bull Simulate drug dissolution in GI tract for Ibuprofen IR formulation and Mesalamine MR formulations (Pentasa Apriso Lialda) and validate the model using clinical data (drug concentration in GI tract)

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Directly Measure In Vivo Drug Dissolution in Human GI tract by

Clinical Intubation Study

27

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations

bull Modified release formulations of mesalamine in comparison of oral solutionbull Pentasa 500 mg capsule x 2

bull Apriso 375 mg capsule x 3

bull Lialda 1200 mg tablet x 1

bull Mesalamine oral solution 100 mg125 ml water followed by 125 water

bull Immediate release formulations of ibuprofen bull Fasting State 800 mg Ibuprofen

bull Fed State 800 mg of Ibuprofen

bull Phenol red (100 ugml) as non absorobable maker

28

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

GI Intubation Tube Design

bull Multi-lumen GI tube with Tungstenweighted distal tip

bull 4 aspiration channels and 1channel for guide wire placement

bull Aspiration channels spaced 50 cmapart

bull Manufactured by Arndorfer IncGreendale Wisconsin

bull Length 300 cm

bull Diameter 7 mm

bull Length from mouth to Port 1 100cm

Multi-Lumen GI Tube

29

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Intubation Procedure in Human GI Tract

Port Locations1 Distal Jejunum

Proximal Ileum2 Proximal Jejunum3 Duodenum4 Stomach

Fluoroscopic photo of GI tube placement Shown are 3 aspiration ports located in the stomach proximal jejunum and distal jejunum

1

4

3

2

30

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Sample Collection

bull GI fluids bull Stomach duodenum jejunum early ileum

bull 05-1 mL at each port at 1 2 3 4 5 6 7 hours

bull Bloodbull 025 05 1 2 3 4 6 8 10 12 24 48 72 96 hours

bull Fecesbull 0-12 12-24 24-48 48-72 72-96 hours

31

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Average concentrations of 5-ASA and Ac-5-ASA in different regions of small intestine when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

0

2000

4000

6000

5-A

SA

Ac-5-A

SA

0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8

Time (hr)

Con

ce

ntr

ation

(u

M)

Drug Formulation

Pentasa

Apriso

Lialda

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Concentrations of 5-ASA and Ac-5-ASA in different GI regions for each individual subject when administered a dose of 1000mg Pentasa 1125mg Apriso or 1200mg Lialda

Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum

0

2000

4000

6000

010002000300040005000

0

100020003000

4000

0

500

1000

1500

0

20

40

60

05

10152025

PentasaPentasa

AprisoApriso

LialdaLialda

5-ASAAc-5-ASA

5-ASAAc-5-ASA

5-ASAAc-5-ASA

0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6 0 2 4 6

Time (hr)

Con

cent

ratio

n (u

M)

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0 10 20 0 10 20

Time (hr)

Concentr

atio

n (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates

Fasted Fed

0

25000

50000

75000

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+05

0e+00

2e+05

4e+05

6e+058e+05

Pla

sm

aS

tom

ach

Du

od

en

umP

roxim

al J

eju

nu

mMid

Je

jun

um

0 2 4 6 8 0 2 4 6 8

Time (hr)

Concentr

ation (

ngm

l)

Poster 08W0830 Mark Koenigsknecht

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

UM Clinical Study TeamDuxin Sun PhDGordon L Amidon PhDWilliam L Hasler MD Allen Lee MDJason R Baker MSHiro Tsume PhDAnn Frances Fioritto BS Barry Bleske PharmDMark Koenigsknecht PhDJeff Wysocki RNMICHR nurse team

UM Pharmacokinetics Core Alex YuBo Wen PhD Ying Wang PhD Ruijuan Luo PhD Siwei Li PhDTing Zhao PhD

Subjects ndash Healthy Volunteers

Acknowledgment

UM Department of MathematicsTrachette Jackson PhD

FDA CDER OGDRobert Lionberger PhDXinyuan (Susie) Zhang PhDJeff Jiang PhDJianhong Fan PhDAndrew Babiskin PhDThushi Amini PhD Hong Wen PhD

Duxin Sun Lab

Acknowledgment

Duxin Sun Lab

Acknowledgment