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

Transcription

1 Modeling Dynamic Gastrointestinal Fluid Transit as a Basis for Dissolution and Absorption Duxin Sun, Ph.D. 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

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

3 Compartmental Approach has Demonstrated Some Success in Predicting Oral Absorption Question: is there in vivo consideration of GI fluid volume?

4 Three Compartment Models Compared: Static Volume per Compartment Assumption Physiological Parameters for the Evaluated Intestinal Absorption Models Included in Simcyp (SC), GastroPlus (G+), and GI-Sim (GS) volume (ml) transit time (min) ph GI compartment SC b G+ GS SC G+ GS SC G+ GS Sjögren et al. In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models Mol. Pharmaceutics, 2016, 13 (6), pp

5 Static Volume Assumption Leads Primarily to Mass Driven Absorption Primary terms for calculating absorption ACAT: Absorption ( dm dt ) = k i av (i) (C i L C i E ) ADAM: dc ent,n dt = 1 V ent,n (A diss,n ka n ) Rate of absorption differs between compartments 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

6 Dynamic Fluid Model Reflects in vivo GI Volume Changes Traditional Approach Estimation V(n) Solid Dissolution M n (t) M n (t) Absorption Estimation Dissolution New Dynamic Volume Approach V n (t) Solid Dissolution M n (t) C n (t) Absorption Absorption Dissolution Absorption

7 Transit to Colon Dynamic Fluid Compartment Absorption and Transport Model Stomach Small Intestine Poster 09T0200 Alex Yu Drug M S M I1 M I2 M I3 M I,n M I30 Fluid V S V I1 V I2 V I3 V I,n V I30 Secretion/Absorption Systemic Circulation Defining Attributes Thirty small intestine compartments in series Forward and retrograde transit Net secretion in the stomach Secretion and absorption in duodenum Net absorption throughout the rest of small intestine

8 Impact of Unknown Volume in GI Tract Previously no available data of in vivo GI volume Generates uncertainty for basis in in vitro drug dissolution conditions and in vivo drug dissolution prediction. MRI study in human has provided total volume of stomach, small intestine, and colon, it did not provide volume of each segment of GI tract 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

9 Measurement of Gastrointestinal (GI) Fluid Volume using MRI Mol Pharm Sep 2;11(9): doi: /mp500210c. Epub 2014 Aug 19. Quantification of gastrointestinal liquid volumes and distribution following a 240 ml dose of water in the fasted state. Mudie DM 1, Murray K, Hoad CL, Pritchard SE, Garnett MC, Amidon GL, Gowland PA, Spiller RC, Amidon GE, Marciani L.

10 Gastric liquid volume (ml) Stomach Fluid Transport Analysis mL water drink study Gastric liquid volumes n=12 (mean±sem) Time (min) Water Intake 240mL Secretion k ss Stomach V S Assume: Zero order secretion (constant) First order emptying Define terms based on best fit Emptying k qs Mol Pharm Sep 2;11(9): doi: /mp500210c. Epub 2014 Aug 19. Quantification of gastrointestinal liquid volumes and distribution following a 240 ml dose of water in the fasted state. Mudie DM 1, Murray K, Hoad CL, Pritchard SE, Garnett MC, Amidon GL, Gowland PA, Spiller RC, Amidon GE, Marciani L.

11 Stomach Fluid Transport Analysis Simulation in Blue. Clinically Measured Volume using MRI in Red

12 Fluid Transport Analysis of Stomach and Small Intestine Secretion k ss Secretion k si Water Intake 240mL Stomach V S Emptying k qs Intestine V I Exit to Colon Absorption k wa Literature based estimation First order absorption Two Unknowns to Estimate Secretion and Exit to Colon (dependent on transit speed) Minimal

13 Residual Analysis Based on Small Intestine MRT to Develop The Intestinal Fluid Transit Model Surface plot indicates residual (z axis) (blue is low) Overall cumulative exit is similar to MRT in small intestine as previously reported Adv Drug Del Rev Jun 12, 19(3) doi: / X(96) Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption Lawrence X. Yu a, 1, Elke Lipka b, John R. Crison b, Gordon L. Amidon

14 MRI Measurement and Modeling of Small Intestinal Fluid Mol Pharm Sep 2;11(9): doi: /mp500210c. Epub 2014 Aug 19. Quantification of gastrointestinal liquid volumes and distribution following a 240 ml dose of water in the fasted state. Mudie DM 1, 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

15 MRI Measurement and Modeling of Upper and Lower Small Intestinal Fluid Upper/Lower small intestine fluid volumes were quantified in the MRI study.

16 Clinical Evaluation of Dynamic Fluid Transit Model by GI Intubation and Measurement of Non-absorbable Marker in the GI tract Fasted healthy volunteers Dose 240mL of Phenol Red (Non-absorbable marker) Clinical GI Intubation Study Multi-lumen GI tube 4 aspiration ports to obtain GI samples Multi-Lumen GI Tube

17 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

18 Case Study: Apply Dynamic Fluid Transit Model to Predict PK Profile after Oral Dosing of Mesalamine Solution Human volunteers Drug: 125 ml Mesalamine100 mg oral solution, followed by 125 ml water Measure mesalamine plasma concentration for pharmacokinetic parameters analysis Apply dynamic fluid transit model to simulate plasma drug profile Compare with traditional CAT model to simulate plasma drug profile

19 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 ASA Ac-5-ASA Concentration (nm) Drug Formulation Pentasa Apriso Lialda Solution Time (hr)

20 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. 5-ASA 25 Solution 30 Pentasa Concentration (nm) Apriso Lialda Time (hr)

21 Dynamic Fluid Models Can Better Characterize the Early Absorption Process

22 Dynamic Fluid Transit Model can also be Tuned for the Stomach Volume in Individual Subject Blue: Simulation Red: MRI measurement

23 Dynamic Fluid Transit Model can also be Tuned for the Small Intestine in Individual Subject Blue: Simulation Red: MRI measurement

24 Visualization of Dynamic Fluid Volume Changes and Concentration Gradient in 30 Compartments of GI tract After dosing mesalamine Solution 100mg Model depicts physical transit through GI Left (Duodenum) to Right (Ileum) Three different individuals Low Concentration High Concentration

25 Dynamic Fluid Changes in GI Tract Alter Mesalamine Plasma Profile in Different Individuals Same 100mg solution dosing Same pharmacokinetic parameters Only dynamic volume has changed

26 Summary 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 Dynamic fluid model simulates drug concentration in GI tract and in plasma after oral solution dosing Future studies Refine the model to simulate concentration of nonabsorbable marker (Phenol red) in GI tract and validate the model with clinical data (GI concentration in GI tract) Add MMC into current Dynamic fluid model? 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)

27 Directly Measure In Vivo Drug Dissolution in Human GI tract by Clinical Intubation Study 27

28 In Vivo GI tract Dissolution of Modified Release Formulations and Immediate Release Formulations Modified release formulations of mesalamine in comparison of oral solution Pentasa : 500 mg capsule x 2 Apriso : 375 mg capsule x 3 Lialda : 1200 mg tablet x 1 Mesalamine oral solution: 100 mg/125 ml water, followed by 125 water Immediate release formulations of ibuprofen Fasting State: 800 mg Ibuprofen Fed State: 800 mg of Ibuprofen Phenol red (100 ug/ml) as non absorobable maker 28

29 GI Intubation Tube Design Multi-Lumen GI Tube Multi-lumen GI tube with Tungsten weighted distal tip 4 aspiration channels and 1 channel for guide wire placement Aspiration channels spaced 50 cm apart Manufactured by Arndorfer, Inc., Greendale, Wisconsin Length: 300 cm Diameter: 7 mm Length from mouth to Port 1: 100 cm 29

30 Intubation Procedure in Human GI Tract Port Locations: 1. Distal Jejunum/ Proximal Ileum 2. Proximal Jejunum 3. Duodenum 4. Stomach Fluoroscopic photo of GI tube placement. Shown are 3 aspiration ports located in the stomach, proximal jejunum, and distal jejunum. 30

31 Sample Collection GI fluids Stomach, duodenum, jejunum, early ileum ml at each port at 1, 2, 3, 4, 5, 6, 7 hours Blood 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours Feces 0-12, 12-24, 24-48, 48-72, hours 31

32 5-ASA Ac-5-ASA 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 6000 Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum 4000 Concentration (um) Drug Formulation Pentasa Apriso Lialda Time (hr)

33 5-ASA Ac-5-ASA 5-ASA Ac-5-ASA 5-ASA Ac-5-ASA Pentasa Pentasa Apriso Apriso Lialda 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. Concentration (um) Stomach Duodenum Proximal Jejunum Jejunum Distal Jejunum Time (hr)

34 Plasma Ibuprofen Concentration After 800 mg Dose at Fasted and Fed Sates Poster 08W0830 Mark Koenigsknecht Fasted Fed Concentration (ng/ml) Time (hr)

35 Plasma Stomach DuodenumProximal JejunumMid Jejunum Ibuprofen Concentration in Human GI Tract After 800 mg Dose at Fasted and Fed Sates Poster 08W0830 Mark Koenigsknecht Fasted Fed Concentration (ng/ml) 6e+05 4e+05 2e+05 0e+00 6e+05 4e+05 2e+05 0e+00 6e+05 4e+05 2e+05 0e+00 8e+05 6e+05 4e+05 2e+05 0e Time (hr)

36 Acknowledgment UM Clinical Study Team Duxin Sun, Ph.D. Gordon L Amidon, Ph.D. William L. Hasler, M.D. Allen Lee, MD Jason R. Baker, M.S. Hiro Tsume, Ph.D. Ann Frances Fioritto, B.S. Barry Bleske, Pharm.D. Mark Koenigsknecht, Ph.D. Jeff Wysocki, R.N. MICHR nurse team UM Pharmacokinetics Core Alex Yu Bo Wen, Ph.D. Ying Wang, Ph.D. Ruijuan Luo, Ph.D. Siwei Li, Ph.D. Ting Zhao, Ph.D. UM Department of Mathematics Trachette Jackson, PhD Subjects Healthy Volunteers FDA, CDER, OGD Robert Lionberger, Ph.D. Xinyuan (Susie) Zhang, Ph.D. Jeff Jiang, Ph.D. Jianhong Fan, Ph.D. Andrew Babiskin, Ph.D. Thushi Amini, Ph.D. Hong Wen, Ph.D.

37 Duxin Sun Lab Acknowledgment