Poster Number
`
`P682
`
`Multiple-Dose Pharmacokinetics of Granulated Mesalamine, a Unique Formulation Providing Delayed and Extended Release of 5-ASA
`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
`
`InTRODUCTIOn
`
`
`•
`
`•
`
`•
`
` –
` –
`
` –
`
` –
`
`•
`
`2
`
`1
`
`3
`
`METHODS
`Participant selection
`Inclusion criteria
`•
` –
`Healthy adults 18 to 45 years old
`Study design
`Crossover study design (Figure 2)
`•
`Plasma, urine, and fecal samples were collected to determine relative absorption
`•
`and excretion
`Plasma PK parameters
`Baseline blood samples were collected before dosing on morning of day 4 of
`•
`each treatment period (Figure 2)
`Additional samples were collected over 24 h after dose on day 4 of each
`treatment period
`Figure 2. Study design and PK sampling schedule.
`
`•
`
`Feces and urine
`
`Collected days 1-4
`Analyzed for each 24-h interval within treatment period
`
`table 1. Participant Demographics
`
`
`Characteristic
`Mean age (range), y
`
`Male:Female, n
`
`Race, n (%)
`
` White
`
` Hispanic/Latino
`
` Asian/Pacific Islander
`
` Black
`
`Mean weight, kg
`
`RESULTS
`30 participants were randomized into study, 28 completed both treatment periods (Table 1)
`•
`
`T• max values for 5-ASA and N-Ac-5-ASA were shorter for GM q.d. dosing (3 h) than b.i.d.
`dosing (approximately 4 h after second daily dose; Figure 3)
`Figure 3. Mean 5-ASA plasma concentration by treatment group over time, linear scale; arrows indicate Tmax for
`GM q.d. and b.i.d. dosing regimens.
`
`Tmax
`
`GM 1600 mg q.d.
`(n=28)
`
`GM 800 mg b.i.d.
`(n=28)
`
`Tmax
`
`0 1
`
`32
`
`4
`
`6
`
`8
`
`10
`12
`Time, h
`
`16
`
`20
`
`24
`
`N-Ac-5-ASA was comparable
`
`18
`
`16
`
`14
`
`12
`
`10
`
`02468
`
`Mean plasma 5-ASA, µmol/L
`
`Participants
`(N=30)
`27 (19-45)
`
`25:5
`
`22 (73)
`
`5 (17)
`
`2 (7)
`
`1 (3)
`
`76.5
`
`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
` –
`regimens7
`Granulated mesalamine (GM) is first 5-ASA formulation to provide delayed and
`extended release with once-daily (q.d.) dosing (Figure 1)
`
` –
`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
`less-frequent dosing regimen7
`Once-daily administration of GM may improve patient adherence, resulting in
`better therapeutic efficacy7
`Pharmacokinetics (PK) of once- or twice-daily (b.i.d.) administration of GM
`were compared in this phase 1, crossover trial
`
`•
`
`•
`
`Figure 1. Schematic of granulated mesalamine formulation.
`
`Polymer matrix core
`contains 5-ASA,
`which is released over
`a 6- to 7-hour period
`
`External coating
`
`Enteric film coating,
`dissolves at pH ≥6
`
`Inner core surrounded by enteric pH-dependent coating allows for delayed and extended release of 5-ASA.
`OBJECTIVE
`To compare PK, tolerability, and safety of GM 1600 mg q.d. and 800 mg b.i.d.
`•
`
`Randomization
`
`1600 mg q.d.
`
`4 days –
`PK sampling
`period 1
`
`800 mg b.i.d.
`
`Washout
`≥7 days
`
`800 mg b.i.d.
`
`4 days –
`PK sampling
`period 2
`
`1600 mg q.d.
`
`Plasma
`
`Baseline plasma sample collected before dosing on day 4
`Samples for PK analysis taken over 24-h period after day 4 dose
`
`Single-center, randomized, open-label, phase 1 study. Participants were randomized to receive GM 1600 mg (two 800-mg unit
`doses) q.d. or 800 mg b.i.d.
`
`Fecal and urinary PK parameters
`All stool and urine samples collected each day of both treatment periods (Figure 2)
`•
`Concentrations of 5-ASA and its metabolite,
`N-acetyl-5-ASA (N-Ac-5-ASA), were
`•
`measured
`Cumulative urine 5-ASA plus N-Ac-5-ASA
`
` –
`
`Cumulative fecal 5-ASA plus N-Ac-5-ASA
` –
`Safety
`Assessment included observation of clinical laboratory parameters, vital signs, physical
`•
`examination, and adverse events (AEs)
`
`Plasma PK
`Although neither area under the concentration-time curve (AUC) nor maximum plasma
`•
`concentration (Cmax) met the traditional bioequivalency statistical criteria
`Systemic exposure (as measured by AUC) to 5-ASA and
` –
`N-Ac-5-ASA was comparable between
`GM q.d. and b.i.d. regimens (Table 2)
`
`In contrast, mean Cmax of 5-ASA and N-Ac-5-ASA were slightly higher in q.d. regimen than in b.i.d.
`regimen
`
` –
`
`table 2. Plasma Pharmacokinetics (Mean ± Standard Deviation)
`
`Granulated
`Granulated
`mesalamine
`mesalamine
`1600 mg q.d.
`800 mg b.i.d.
`
`Ratio q.d./b.i.d.
`(90% CI)a
`
`Fecal and urinary excretion
`•
`Mean cumulative fecal excretion of 5-ASA plus
`between regimens
`Mean cumulative urinary excretion of 5-ASA plus
`between regimens
`Safety and tolerability
`•
`Most commonly reported AE during q.d. and b.i.d. treatment periods was headache
`(n=2 and n=3, respectively)
`Erythema was the only other AE reported in both treatment groups
`All AEs that participants experienced during both treatment periods were mild or
`moderate in intensity; no severe AEs were reported
`
`•
`
`•
`•
`
`N-Ac-5-ASA was comparable
`
`Parameter
`Cmax, μg/mL
` 5-ASA
`
` N-Ac-5-ASA
`
`AUC, μg•h/mL
`
` 5-ASAc
`
` N-Ac-5-ASAc
`Tmax, h
` 5-ASAd
`
`3.0 ± 1.7
`
`4.5 ± 1.8
`
`1.8 ± 0.7
`
`3.6 ± 1.2
`
`153 (113-208)b
`
`118 (98-143)
`
`14.8 ± 6.5
`
`45.8 ± 19.7
`
`14.8 ± 5.5
`
`46.4 ± 15.4
`
`96 (76-121)
`
`93 (78-112)
`
`3.0 (2.0-16.0)
`
`16.0 (2-24.0)
`
`—
`
`DISCUSSIOn anD COnCLUSIOnSab
`
`•
`
`•
`
`•
`
`Comparable systemic absorption of delayed- and extended-release
`GM formulation whether administered q.d. or b.i.d.
`Similarity in PK between GM dosing regimens supports convenient,
`once-daily dosing and may reduce pill burden
`GM is first formulation to provide delayed and extended release of 5-ASA
`a For analysis of effect of high-fat meal on PK of GM, please refer to poster P681.
`b For efficacy and safety analysis of GM, please refer to posters P279 and P673.
`
` N-Ac-5-ASAd
`—
`16.0 (2-24.0)
`3.0 (2.0-24.0)
`CI, confidence interval; Tmax, time to maximum plasma concentration. a Ratios calculated from geometric means of log transformed
`results; ratios multiplied by 100. b P=0.02. c Median (range). c Values represent AUC from time 0 to time 24 h for both formulations.
`d Median (range).
`
`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. Brunner M, Assandri R, Kletter K, et al. Aliment Pharmacol Ther. 2003;17(3):395-402.
`
`Presented at American College of Gastroenterology Annual Scientific Meeting • October 3–8, 2008; Orlando, FL
`
`Dr. Falk Ex. 2046
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`P682
`
`Multiple-Dose Pharmacokinetics of Granulated Mesalamine, a Unique Formulation Providing Delayed and Extended Release of 5-ASA
`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
`
`InTRODUCTIOn
`
`
`•
`
`•
`
`•
`
` –
` –
`
` –
`
` –
`
`•
`
`2
`
`1
`
`3
`
`METHODS
`Participant selection
`Inclusion criteria
`•
` –
`Healthy adults 18 to 45 years old
`Study design
`Crossover study design (Figure 2)
`•
`Plasma, urine, and fecal samples were collected to determine relative absorption
`•
`and excretion
`Plasma PK parameters
`Baseline blood samples were collected before dosing on morning of day 4 of
`•
`each treatment period (Figure 2)
`Additional samples were collected over 24 h after dose on day 4 of each
`treatment period
`Figure 2. Study design and PK sampling schedule.
`
`•
`
`Feces and urine
`
`Collected days 1-4
`Analyzed for each 24-h interval within treatment period
`
`table 1. Participant Demographics
`
`
`Characteristic
`Mean age (range), y
`
`Male:Female, n
`
`Race, n (%)
`
` White
`
` Hispanic/Latino
`
` Asian/Pacific Islander
`
` Black
`
`Mean weight, kg
`
`RESULTS
`30 participants were randomized into study, 28 completed both treatment periods (Table 1)
`•
`
`T• max values for 5-ASA and N-Ac-5-ASA were shorter for GM q.d. dosing (3 h) than b.i.d.
`dosing (approximately 4 h after second daily dose; Figure 3)
`Figure 3. Mean 5-ASA plasma concentration by treatment group over time, linear scale; arrows indicate Tmax for
`GM q.d. and b.i.d. dosing regimens.
`
`Tmax
`
`GM 1600 mg q.d.
`(n=28)
`
`GM 800 mg b.i.d.
`(n=28)
`
`Tmax
`
`0 1
`
`32
`
`4
`
`6
`
`8
`
`10
`12
`Time, h
`
`16
`
`20
`
`24
`
`N-Ac-5-ASA was comparable
`
`18
`
`16
`
`14
`
`12
`
`10
`
`02468
`
`Mean plasma 5-ASA, µmol/L
`
`Participants
`(N=30)
`27 (19-45)
`
`25:5
`
`22 (73)
`
`5 (17)
`
`2 (7)
`
`1 (3)
`
`76.5
`
`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
` –
`regimens7
`Granulated mesalamine (GM) is first 5-ASA formulation to provide delayed and
`extended release with once-daily (q.d.) dosing (Figure 1)
`
` –
`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
`less-frequent dosing regimen7
`Once-daily administration of GM may improve patient adherence, resulting in
`better therapeutic efficacy7
`Pharmacokinetics (PK) of once- or twice-daily (b.i.d.) administration of GM
`were compared in this phase 1, crossover trial
`
`•
`
`•
`
`Figure 1. Schematic of granulated mesalamine formulation.
`
`Polymer matrix core
`contains 5-ASA,
`which is released over
`a 6- to 7-hour period
`
`External coating
`
`Enteric film coating,
`dissolves at pH ≥6
`
`Inner core surrounded by enteric pH-dependent coating allows for delayed and extended release of 5-ASA.
`OBJECTIVE
`To compare PK, tolerability, and safety of GM 1600 mg q.d. and 800 mg b.i.d.
`•
`
`Randomization
`
`1600 mg q.d.
`
`4 days –
`PK sampling
`period 1
`
`800 mg b.i.d.
`
`Washout
`≥7 days
`
`800 mg b.i.d.
`
`4 days –
`PK sampling
`period 2
`
`1600 mg q.d.
`
`Plasma
`
`Baseline plasma sample collected before dosing on day 4
`Samples for PK analysis taken over 24-h period after day 4 dose
`
`Single-center, randomized, open-label, phase 1 study. Participants were randomized to receive GM 1600 mg (two 800-mg unit
`doses) q.d. or 800 mg b.i.d.
`
`Fecal and urinary PK parameters
`All stool and urine samples collected each day of both treatment periods (Figure 2)
`•
`Concentrations of 5-ASA and its metabolite,
`N-acetyl-5-ASA (N-Ac-5-ASA), were
`•
`measured
`Cumulative urine 5-ASA plus N-Ac-5-ASA
`
` –
`
`Cumulative fecal 5-ASA plus N-Ac-5-ASA
` –
`Safety
`Assessment included observation of clinical laboratory parameters, vital signs, physical
`•
`examination, and adverse events (AEs)
`
`Plasma PK
`Although neither area under the concentration-time curve (AUC) nor maximum plasma
`•
`concentration (Cmax) met the traditional bioequivalency statistical criteria
`Systemic exposure (as measured by AUC) to 5-ASA and
` –
`N-Ac-5-ASA was comparable between
`GM q.d. and b.i.d. regimens (Table 2)
`
`In contrast, mean Cmax of 5-ASA and N-Ac-5-ASA were slightly higher in q.d. regimen than in b.i.d.
`regimen
`
` –
`
`table 2. Plasma Pharmacokinetics (Mean ± Standard Deviation)
`
`Granulated
`Granulated
`mesalamine
`mesalamine
`1600 mg q.d.
`800 mg b.i.d.
`
`Ratio q.d./b.i.d.
`(90% CI)a
`
`Fecal and urinary excretion
`•
`Mean cumulative fecal excretion of 5-ASA plus
`between regimens
`Mean cumulative urinary excretion of 5-ASA plus
`between regimens
`Safety and tolerability
`•
`Most commonly reported AE during q.d. and b.i.d. treatment periods was headache
`(n=2 and n=3, respectively)
`Erythema was the only other AE reported in both treatment groups
`All AEs that participants experienced during both treatment periods were mild or
`moderate in intensity; no severe AEs were reported
`
`•
`
`•
`•
`
`N-Ac-5-ASA was comparable
`
`Parameter
`Cmax, μg/mL
` 5-ASA
`
` N-Ac-5-ASA
`
`AUC, μg•h/mL
`
` 5-ASAc
`
` N-Ac-5-ASAc
`Tmax, h
` 5-ASAd
`
`3.0 ± 1.7
`
`4.5 ± 1.8
`
`1.8 ± 0.7
`
`3.6 ± 1.2
`
`153 (113-208)b
`
`118 (98-143)
`
`14.8 ± 6.5
`
`45.8 ± 19.7
`
`14.8 ± 5.5
`
`46.4 ± 15.4
`
`96 (76-121)
`
`93 (78-112)
`
`3.0 (2.0-16.0)
`
`16.0 (2-24.0)
`
`—
`
`DISCUSSIOn anD COnCLUSIOnSab
`
`•
`
`•
`
`•
`
`Comparable systemic absorption of delayed- and extended-release
`GM formulation whether administered q.d. or b.i.d.
`Similarity in PK between GM dosing regimens supports convenient,
`once-daily dosing and may reduce pill burden
`GM is first formulation to provide delayed and extended release of 5-ASA
`a For analysis of effect of high-fat meal on PK of GM, please refer to poster P681.
`b For efficacy and safety analysis of GM, please refer to posters P279 and P673.
`
` N-Ac-5-ASAd
`—
`16.0 (2-24.0)
`3.0 (2.0-24.0)
`CI, confidence interval; Tmax, time to maximum plasma concentration. a Ratios calculated from geometric means of log transformed
`results; ratios multiplied by 100. b P=0.02. c Median (range). c Values represent AUC from time 0 to time 24 h for both formulations.
`d Median (range).
`
`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. Brunner M, Assandri R, Kletter K, et al. Aliment Pharmacol Ther. 2003;17(3):395-402.
`
`Presented at American College of Gastroenterology Annual Scientific Meeting • October 3–8, 2008; Orlando, FL
`
`Dr. Falk Ex. 2046
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
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