Poster Number
`
`P681
`
`INTRODUCTION
`
`Minimal Effect of a High-Fat Meal on the Pharmacokinetics of Once-Daily Granulated Mesalamine
`A Safdi,1 H Pieniaszek,2 A Grigston,3 W Forbes3
`1Ohio Gastroenterology & Liver Institute, Cincinnati, OH; 2HPP Consulting & Services, Inc, Darlington, MD; 3Salix Pharmaceuticals, Inc, Morrisville, NC
`
`Ulcerative colitis (UC) is chronic inflammatory disease of colon
`Affects more than 500,000 individuals in United States
` –
`Treatment goals include induction and maintenance of remission
` –
`Oral 5-aminosalicylate (5-ASA) is safe and effective treatment for adults with mild-to-
` –
`moderate UC4,5
`Patient adherence to treatment is poor when remission of UC has been
`achieved, increasing risk of UC flare6
`Poor adherence is attributed in part to high pill burden and inconvenient dosing regimens
` –
`Granulated mesalamine (GM) is first 5-ASA formulation to provide delayed and
`extended release with once-daily dosing
`
` –
`Outer coating dissolves at pH ≥6, delivering 5-ASA directly to terminal ileum and colon
`Polymer matrix core facilitates slow release and distribution in colon
` –
`Steady delivery of 5-ASA to terminal ileum and colon may minimize systemic
` –
`absorption and potential for adverse events8
`Granulated mesalamine is approved for use in Europe for treatment and maintenance
`of remission of UC
`Currently being reviewed by Food and Drug Administration for maintenance of
`UC remission
`Patient adherence to 5-ASA treatment may improve with well-tolerated and
`once-daily dosing regimen7,8
`Pharmacokinetics (PK) of oral 5-ASA agents may be altered when administered
`with food,9 potentially affecting efficacy and safety of treatment
`
`•
`
`Mean plasma 5-ASA concentrations were comparable between fed and fasted conditions
`for 24 hours after GM administration (Figure 2)
`Figure 2. Mean plasma concentration of 5-ASA by condition over time.
`
`•
`
`•
`
`N-Ac-5-ASA was significantly higher (17%; P=0.04) in participants who
`Fecal excretion of
`received GM after high-fat meal compared with N-Ac-5-ASA levels after fasting
`Fecal excretion of 5-ASA plus
`N-Ac-5-ASA was similar in fasted and fed conditions
`
`Safety and tolerability
`•
`All reported AEs were mild or moderate in severity
`No severe AEs or discontinuations due to AEs were reported
`•
`Headache was most commonly reported AE during both fasted (n=3) and fed (n=3)
`•
`treatment regimens
`Abdominal pain was the only other AE reported in more than 1 participant (1 each in
`fasted and fed conditions)
`
`•
`
`DISCUSSION aND CONCLUSIONSab
`
`•
`
`Study demonstrates ability to administer delayed- and extended-release GM
`formulation without regard to food
`
`•
`
`PK parameters of single-dose GM 1600 mg were notably comparable after
`ingestion of high-fat meal and after fasting
`
`•
`
`N-Ac-5-ASA were
`
`Fasted, GM 1600 mg
`(N=30)
`
`Fed, GM 1600 mg
`(N=30)
`
`14
`
`12
`
`10
`
`02468
`
`Mean plasma 5-ASA, µmol/L
`
`Participants
`(N=30)
`24
`23:7
`
`26 (87)
`1 (3)
`3 (10)
`72.4
`
`0 1
`
`32
`
`4
`
`6
`
`8
`10
`12
`16
`Post-dose time, h
`
`20
`
`24
`
`
`
`RESULTS
`30 participants were randomized into study (Table 1)
`•
`
`table 1. Participant Demographics
`
`
`Characteristic
`Mean age, y
`Male:Female, n
`Race, n (%)
` White
` Black
` Other
`Mean weight, kg
`
`•
`
`7
`
`2
`
`1
`
`3
`
`•
`
`•
`
`•
`
`•
`
`•
`
` –
`
` –
`
`Fasted versus fed plasma PK
`PK of 5-ASA and
`•
`N-Ac-5-ASA for fed and fasted states are summarized in Table 2
`
`•
`Ingestion of high-fat meal increased time to maximum plasma concentration (Tmax) for
`both 5-ASA and N-Ac-5-ASA compared with Tmax values after fasting
`
`Maximum plasma concentration (Cmax) levels of both analytes were comparable and
`bioequivalent for fasted and fed conditions
`Slightly higher area under the concentration-time curve from time zero to infinity (AUCinf)
`
`for 5-ASA was observed in fed condition (11%) versus in fasted condition but is probably
`not clinically significant (Table 2)
`
`In fed condition, 6% increase in AUCinf was observed versus in fasted condition when
`calculated using arithmetic means
`
`•
`
`•
`
`table 2. Plasma Pharmacokinetics (Mean ± Standard Deviation)
`
`
`Fed
`(N=30)
`
`2.5 ± 1.3
`3.6 ± 1.4
`
`13.8 ± 5.7
`43.4 ± 23.6
`
`Fed/Fasted ratio
`(90% CI)a
`
`104 (87-125)
`103 (90-117)
`
`111 (96-128)
`95 (84-108)
`
`Fasted
`(N=30)
`
`2.6 ± 1.4
`3.7 ± 1.8
`
`13.0 ± 6.1
`44.9 ± 18.5
`
`Parameter
`Cmax, μg/mL
` 5-ASA
` N-Ac-5-ASA
`AUCinf, μg•h/mL
` 5-ASA
` N-Ac-5-ASA
`Tmax, h
` 5-ASAb
` N-Ac-5-ASAb
`
`4.0 (3.0-8.0)c
`6.0 (2.0-16.0)c
`
`8.0 (3.0-20.0)c
`8.0 (3.0-24.0)c
`
`—
`—
`
`CI, confidence interval. a Ratios and CIs calculated from geometric means of log transformed results; ratios multiplied by 100.
`b P<0.001; calculated from signed rank test. c Median (range).
`
`OBJECTIVE
`N-acetyl-5-ASA (N-Ac-5-ASA), in participants
`To evaluate PK of 5-ASA and its metabolite,
`•
`who received once-daily (q.d.) GM 1600 mg (two 800-mg unit doses) after fasting and
`after high-fat meal
`METHODS
`Participant selection
`Inclusion criteria
`•
`Healthy adults between ages of 18 and 45 y
` –
`Study design
`Crossover study design (Figure 1)
`•
`Figure 1. Study design and PK sampling schedule.
`
`Feces and urine
`
`Collected days 1-4
`Analyzed for each 24-h interval within treatment period
`
`Randomization
`
`High-fat meal
`1600 mg
`
`4 days –
`PK sampling
`period 1
`1600 mg
`Fasted
`
`Washout
`7-10 days
`
`Fasted
`1600 mg
`
`4 days –
`PK sampling
`period 2
`1600 mg
`High-fat meal
`
`Plasma
`
`Baseline plasma sample collected before dosing on day 1
`Samples for PK analysis taken over 24-h period after day 1 dose
`
`Single-center, randomized, open-label, crossover, phase 1 study.
`
`Similar cumulative fecal and urinary excretion of 5-ASA and
`observed after fasting or high-fat meal
`
`•
`
`All AEs were mild or moderate in severity
`
`a For PK analysis and comparison of once- and twice-daily administration of GM, please see poster P682.
`b For analysis of efficacy and safety of GM, please refer to posters P279 and P673.
`
`Support for preparation of poster provided by Salix Pharmaceuticals, Inc.
`1700 Perimeter Park Drive, Morrisville, NC 27560
`
`References: 1. Kane SV, Bjorkman DJ. Rev Gastroenterol Disord. 2003;3(4):210-218. 2. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Gut.
`2000;46(3):336-343. 3. Gionchetti P, Amadini C, Rizzello F, Venturi A, Campieri M. Aliment Pharmacol Ther. 2002:16(suppl 4):13-19. 4. Sandborn WJ. J Clin Gastroenterol. 2008;42(4):338-344.
`5. Karagozian R, Burakoff R. Ther Clin Risk Manag. 2007;3(5):893-903. 6. Kane SV, Cohen RD, Aikens JE, Hanauer SB. Am J Gastroenterol. 2001;96(10):2929-2933. 7. Tindall WN, Boltri JM,
`Wilhelm SM. J Manag Care Pharm. 2007;13(7 suppl A)S2-S12. 8. Kane SV. Aliment Pharmacol Ther. 2006;23(5):577-585. 9. Yu DK, Elvin AT, Morrill B, et al. Clin Pharmacol Ther. 1990;48(1):26-33.
`
`Urinary excretion
`N-Ac-5-ASA and of 5-ASA plus N-Ac-5-ASA was not significantly
`Urinary excretion of
`•
`different in fasted versus fed conditions (Table 3)
`
`
`table 3. Cumulative Urinary Excretion of 5-ASA and N-Ac-5-ASA After Fasting and After High-Fat Meal (Mean ±
`Standard Deviation)
`
`
`Analyte
`5-ASA, mmol
`N-Ac-5-ASA, mmol
`5-ASA plus N-Ac-5-ASA, mmol
`
`Fasted
`(N=30)
`0.2 ± 0.2
`3.1 ± 1.0
`3.3 ± 1.1
`
`Fed
`(N=30)
`0.3 ± 0.2
`3.1 ± 1.2
`3.3 ± 1.4
`
`Fed/Fasted
`ratio (90% CI)a
`127 (95-159)
`100 (87-112)
`101 (88-115)
`
`a Based on mixed models fit to untransformed data; ratios multiplied by 100.
`
`Fecal excretion
`After ingestion of high-fat meal, fecal excretion of 5-ASA was significantly lower
`•
`compared with 5-ASA levels after fasting (fed/fasted ratio, 70; 90% confidence interval,
`56-85; P=0.002; Table 4)
`table 4. Cumulative Fecal Excretion of 5-ASA and N-Ac-5-ASA After Fasting and After High-Fat Meal (Mean ±
`Standard Deviation)
`
`
`Analyte
`5-ASA, mmol
`N-Ac-5-ASA, mmol
`5-ASA plus N-Ac-5-ASA, mmol
`
`Fasted
`(N=30)
`1.8 ± 1.1
`1.6 ± 0.6
`3.4 ± 1.3
`
`Fed
`(N=30)
`1.3 ± 0.8
`1.9 ± 1.0
`3.1 ± 1.3
`
`Fed/Fasted ratio
`(90% CI)a
`70 (56-85)
`116 (103-129)
`92 (83-101)
`
`a Based on mixed models fit to untransformed data; ratios multiplied by 100.
`
`Presented at American College of Gastroenterology Annual Scientific Meeting • October 3–8, 2008; Orlando, FL
`
`Dr. Falk Ex. 2047
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`P681
`
`INTRODUCTION
`
`Minimal Effect of a High-Fat Meal on the Pharmacokinetics of Once-Daily Granulated Mesalamine
`A Safdi,1 H Pieniaszek,2 A Grigston,3 W Forbes3
`1Ohio Gastroenterology & Liver Institute, Cincinnati, OH; 2HPP Consulting & Services, Inc, Darlington, MD; 3Salix Pharmaceuticals, Inc, Morrisville, NC
`
`Ulcerative colitis (UC) is chronic inflammatory disease of colon
`Affects more than 500,000 individuals in United States
` –
`Treatment goals include induction and maintenance of remission
` –
`Oral 5-aminosalicylate (5-ASA) is safe and effective treatment for adults with mild-to-
` –
`moderate UC4,5
`Patient adherence to treatment is poor when remission of UC has been
`achieved, increasing risk of UC flare6
`Poor adherence is attributed in part to high pill burden and inconvenient dosing regimens
` –
`Granulated mesalamine (GM) is first 5-ASA formulation to provide delayed and
`extended release with once-daily dosing
`
` –
`Outer coating dissolves at pH ≥6, delivering 5-ASA directly to terminal ileum and colon
`Polymer matrix core facilitates slow release and distribution in colon
` –
`Steady delivery of 5-ASA to terminal ileum and colon may minimize systemic
` –
`absorption and potential for adverse events8
`Granulated mesalamine is approved for use in Europe for treatment and maintenance
`of remission of UC
`Currently being reviewed by Food and Drug Administration for maintenance of
`UC remission
`Patient adherence to 5-ASA treatment may improve with well-tolerated and
`once-daily dosing regimen7,8
`Pharmacokinetics (PK) of oral 5-ASA agents may be altered when administered
`with food,9 potentially affecting efficacy and safety of treatment
`
`•
`
`Mean plasma 5-ASA concentrations were comparable between fed and fasted conditions
`for 24 hours after GM administration (Figure 2)
`Figure 2. Mean plasma concentration of 5-ASA by condition over time.
`
`•
`
`•
`
`N-Ac-5-ASA was significantly higher (17%; P=0.04) in participants who
`Fecal excretion of
`received GM after high-fat meal compared with N-Ac-5-ASA levels after fasting
`Fecal excretion of 5-ASA plus
`N-Ac-5-ASA was similar in fasted and fed conditions
`
`Safety and tolerability
`•
`All reported AEs were mild or moderate in severity
`No severe AEs or discontinuations due to AEs were reported
`•
`Headache was most commonly reported AE during both fasted (n=3) and fed (n=3)
`•
`treatment regimens
`Abdominal pain was the only other AE reported in more than 1 participant (1 each in
`fasted and fed conditions)
`
`•
`
`DISCUSSION aND CONCLUSIONSab
`
`•
`
`Study demonstrates ability to administer delayed- and extended-release GM
`formulation without regard to food
`
`•
`
`PK parameters of single-dose GM 1600 mg were notably comparable after
`ingestion of high-fat meal and after fasting
`
`•
`
`N-Ac-5-ASA were
`
`Fasted, GM 1600 mg
`(N=30)
`
`Fed, GM 1600 mg
`(N=30)
`
`14
`
`12
`
`10
`
`02468
`
`Mean plasma 5-ASA, µmol/L
`
`Participants
`(N=30)
`24
`23:7
`
`26 (87)
`1 (3)
`3 (10)
`72.4
`
`0 1
`
`32
`
`4
`
`6
`
`8
`10
`12
`16
`Post-dose time, h
`
`20
`
`24
`
`
`
`RESULTS
`30 participants were randomized into study (Table 1)
`•
`
`table 1. Participant Demographics
`
`
`Characteristic
`Mean age, y
`Male:Female, n
`Race, n (%)
` White
` Black
` Other
`Mean weight, kg
`
`•
`
`7
`
`2
`
`1
`
`3
`
`•
`
`•
`
`•
`
`•
`
`•
`
` –
`
` –
`
`Fasted versus fed plasma PK
`PK of 5-ASA and
`•
`N-Ac-5-ASA for fed and fasted states are summarized in Table 2
`
`•
`Ingestion of high-fat meal increased time to maximum plasma concentration (Tmax) for
`both 5-ASA and N-Ac-5-ASA compared with Tmax values after fasting
`
`Maximum plasma concentration (Cmax) levels of both analytes were comparable and
`bioequivalent for fasted and fed conditions
`Slightly higher area under the concentration-time curve from time zero to infinity (AUCinf)
`
`for 5-ASA was observed in fed condition (11%) versus in fasted condition but is probably
`not clinically significant (Table 2)
`
`In fed condition, 6% increase in AUCinf was observed versus in fasted condition when
`calculated using arithmetic means
`
`•
`
`•
`
`table 2. Plasma Pharmacokinetics (Mean ± Standard Deviation)
`
`
`Fed
`(N=30)
`
`2.5 ± 1.3
`3.6 ± 1.4
`
`13.8 ± 5.7
`43.4 ± 23.6
`
`Fed/Fasted ratio
`(90% CI)a
`
`104 (87-125)
`103 (90-117)
`
`111 (96-128)
`95 (84-108)
`
`Fasted
`(N=30)
`
`2.6 ± 1.4
`3.7 ± 1.8
`
`13.0 ± 6.1
`44.9 ± 18.5
`
`Parameter
`Cmax, μg/mL
` 5-ASA
` N-Ac-5-ASA
`AUCinf, μg•h/mL
` 5-ASA
` N-Ac-5-ASA
`Tmax, h
` 5-ASAb
` N-Ac-5-ASAb
`
`4.0 (3.0-8.0)c
`6.0 (2.0-16.0)c
`
`8.0 (3.0-20.0)c
`8.0 (3.0-24.0)c
`
`—
`—
`
`CI, confidence interval. a Ratios and CIs calculated from geometric means of log transformed results; ratios multiplied by 100.
`b P<0.001; calculated from signed rank test. c Median (range).
`
`OBJECTIVE
`N-acetyl-5-ASA (N-Ac-5-ASA), in participants
`To evaluate PK of 5-ASA and its metabolite,
`•
`who received once-daily (q.d.) GM 1600 mg (two 800-mg unit doses) after fasting and
`after high-fat meal
`METHODS
`Participant selection
`Inclusion criteria
`•
`Healthy adults between ages of 18 and 45 y
` –
`Study design
`Crossover study design (Figure 1)
`•
`Figure 1. Study design and PK sampling schedule.
`
`Feces and urine
`
`Collected days 1-4
`Analyzed for each 24-h interval within treatment period
`
`Randomization
`
`High-fat meal
`1600 mg
`
`4 days –
`PK sampling
`period 1
`1600 mg
`Fasted
`
`Washout
`7-10 days
`
`Fasted
`1600 mg
`
`4 days –
`PK sampling
`period 2
`1600 mg
`High-fat meal
`
`Plasma
`
`Baseline plasma sample collected before dosing on day 1
`Samples for PK analysis taken over 24-h period after day 1 dose
`
`Single-center, randomized, open-label, crossover, phase 1 study.
`
`Similar cumulative fecal and urinary excretion of 5-ASA and
`observed after fasting or high-fat meal
`
`•
`
`All AEs were mild or moderate in severity
`
`a For PK analysis and comparison of once- and twice-daily administration of GM, please see poster P682.
`b For analysis of efficacy and safety of GM, please refer to posters P279 and P673.
`
`Support for preparation of poster provided by Salix Pharmaceuticals, Inc.
`1700 Perimeter Park Drive, Morrisville, NC 27560
`
`References: 1. Kane SV, Bjorkman DJ. Rev Gastroenterol Disord. 2003;3(4):210-218. 2. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Gut.
`2000;46(3):336-343. 3. Gionchetti P, Amadini C, Rizzello F, Venturi A, Campieri M. Aliment Pharmacol Ther. 2002:16(suppl 4):13-19. 4. Sandborn WJ. J Clin Gastroenterol. 2008;42(4):338-344.
`5. Karagozian R, Burakoff R. Ther Clin Risk Manag. 2007;3(5):893-903. 6. Kane SV, Cohen RD, Aikens JE, Hanauer SB. Am J Gastroenterol. 2001;96(10):2929-2933. 7. Tindall WN, Boltri JM,
`Wilhelm SM. J Manag Care Pharm. 2007;13(7 suppl A)S2-S12. 8. Kane SV. Aliment Pharmacol Ther. 2006;23(5):577-585. 9. Yu DK, Elvin AT, Morrill B, et al. Clin Pharmacol Ther. 1990;48(1):26-33.
`
`Urinary excretion
`N-Ac-5-ASA and of 5-ASA plus N-Ac-5-ASA was not significantly
`Urinary excretion of
`•
`different in fasted versus fed conditions (Table 3)
`
`
`table 3. Cumulative Urinary Excretion of 5-ASA and N-Ac-5-ASA After Fasting and After High-Fat Meal (Mean ±
`Standard Deviation)
`
`
`Analyte
`5-ASA, mmol
`N-Ac-5-ASA, mmol
`5-ASA plus N-Ac-5-ASA, mmol
`
`Fasted
`(N=30)
`0.2 ± 0.2
`3.1 ± 1.0
`3.3 ± 1.1
`
`Fed
`(N=30)
`0.3 ± 0.2
`3.1 ± 1.2
`3.3 ± 1.4
`
`Fed/Fasted
`ratio (90% CI)a
`127 (95-159)
`100 (87-112)
`101 (88-115)
`
`a Based on mixed models fit to untransformed data; ratios multiplied by 100.
`
`Fecal excretion
`After ingestion of high-fat meal, fecal excretion of 5-ASA was significantly lower
`•
`compared with 5-ASA levels after fasting (fed/fasted ratio, 70; 90% confidence interval,
`56-85; P=0.002; Table 4)
`table 4. Cumulative Fecal Excretion of 5-ASA and N-Ac-5-ASA After Fasting and After High-Fat Meal (Mean ±
`Standard Deviation)
`
`
`Analyte
`5-ASA, mmol
`N-Ac-5-ASA, mmol
`5-ASA plus N-Ac-5-ASA, mmol
`
`Fasted
`(N=30)
`1.8 ± 1.1
`1.6 ± 0.6
`3.4 ± 1.3
`
`Fed
`(N=30)
`1.3 ± 0.8
`1.9 ± 1.0
`3.1 ± 1.3
`
`Fed/Fasted ratio
`(90% CI)a
`70 (56-85)
`116 (103-129)
`92 (83-101)
`
`a Based on mixed models fit to untransformed data; ratios multiplied by 100.
`
`Presented at American College of Gastroenterology Annual Scientific Meeting • October 3–8, 2008; Orlando, FL
`
`Dr. Falk Ex. 2047
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
