CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`22-301
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEWg S 2
`
`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NBA
`
`22-301
`
`0ND Division
`
`
`
`
`
`Submission Date(s) '
`
`December 21, 2007
`June 8, 2008
`June 13, 2008
`July 25, 2008
`
`Division of Clinical Pharmacology III
`
`Division of Gastroenterology Products and In-Bom Errors of
`Metabolism
`
`
`
`Salix Pharmaceuticals, Inc.
`
`
`
`
`
`
`
`
`505(b)(2)
`
`0 Oral capsule dosage form contains 0.375 g of mesalamine
`
`(5-aminosalicylic acid, S-ASA)
`
`
`0 Four TRADE NAME capsules once daily (1.5 g/day) with or
`'without food
`
`
`IND 62,1 13
`
`Relevant IND(s)
`
`Submission T e; Code
`
`Formulation;
`
`Strengths; Regimen
`
`
`
`
`
`
`
`Maintenance of remission of ulcerative colitis in patients 18
`ears of ae and older
`
`
`
`Optional Intro-divisional briefing was held on September 29, 2008 in presence of Dr. Dennis
`Bashaw and Dr, Haze-Young Ahn.
`Table of Contents
`
`1
`
`2
`
`3
`4
`
`Executive Summary .................................................................................................................2
`l. 1
`Recommendations ...........-.....................................................................L ......................... 2
`1.2
`Phase IV Commitments ................................................................................................. 2
`
`Summary of Clinical Pharmacology and Biopharmaceutics Findings ........................... 2
`1.3
`Question-Based Review........................................................................................................... 5
`2.1
`General Attributes of the drug ....................................................................................... 5
`2.2
`General Clinical Pharmacology ..................................................................................... 9
`2.4
`Extrinsic Factors .......................................................................................................... 13
`
`General Biopharmaceutics ........................................................................................... 13
`2.5
`Analytical Section ........................................................................................................ 15
`2.6
`Detailed Labeling Recommendations .................................................................................... 17
`Appendices ............................................................................................................................ 20
`4.1
`Proposed Package Insert ............................................................................................. 20
`4.2.
`Individual Study Review ............................................................................................. 28
`4.4
`OCP Filing Form .......................................................................................................... 52
`
`

`

`NDA 22—301 Original
`Review of Clinical Pharmacology
`
`1
`
`1.1
`
`Executive Summary
`
`Recommendations
`
`reviewed the clinical pharmacology and
`The Division of Clinical Pharmacology 3 has
`biopharmaceutics information submitted to NDA 22-301 and found it acceptable from clinical
`pharmacology standpoint provided a mutual agreement regarding the label language can be reached
`between the sponsor and the Agency.
`
`1.2
`
`- Phase IV Commitments
`
`None.
`
`1.3
`
`Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`Overview at Clinical Pharmacology and Biogharmaceutics grogram
`
`In support of NDA 22-301, submitted were final study reports of 11 phase 1/2 clinical trials, three
`phase 3 trials (MPPK 3003, MPPK 3004, MPPK3005) and one in vitro study for drug interaction. Of
`11 submitted studies, three of them were most relevant: a relative BA study evaluating mesalamine
`granules BID and QD and Asacol BID (MPPK 1001), a food effect study (MPPK 1002) and single
`dose and multiple dose PK study (MPPK1003). All other studies were supportive and conducted
`using different formulations from the to-be-marketed formulation. Most of the supportive studies
`were relative BA or food effect study for formulations in development and one PK study were
`conducted in pediatric patients with inflammatory bowel disease.
`
`In the clinical pharmacology and biopharmaceutics program, the sponsor used mesalamine granules
`(MG) in different dosage forms, in sachet (sMG) or in capsules (eMG: TRADE NAME). The to-be—
`marketed product is a capsule containing mesalamine granules which was used in phase 3 clinical
`trials (MPPK 3003, MPPK 3004, and MPPK3005) and one phase 1 PK study (MPPK1003). The
`food effect and relative BA studies (MPPK1001 and MPPKIOOZ) were conducted using mesalamine
`granules (of the same formulation as that in capsule) in sachet. Theses two products were equivalent
`based on an in vitro comparative dissolution study (please, also see CMC review by Dr. Gene W.
`I-Iolbert).
`
`Other than sMG or eMG, several supportive studies including one 12 month phase 3 trial were
`conducted using FMG (Dr.Falk mesalamine granules in sachet).
`The FMG was different
`in
`formulation from MG and manufactured in Europe while MG was manufactured in the US. The
`difference in manufacturing site for modified release products is considered the level 3 change in
`manufacturing site and normally requires a BE study for adequate bridging. Because two products
`were not compared in an in vivo BE study, we do not consider that two products were sufficiently
`bridged. Therefore, the studies conducted using FMG product are considered only supportive. The
`supportive studies pertinent to clinical pharmacology and biopharmaceutics were not reviewed for
`this NDA. However, one study BIO/SAG-16 conducted with radiolabeled FMG was reviewed
`because of a labeling claim based on the study.
`
`Pharmacokin etic characteristics
`
`The pharmacokinetics of mesalamine (5-ASA) and its metabolite, N—Ac—S-ASA, were studied after
`single dose and multiple oral doses of 1.5 g TRADE NAME (QD, 4 x 375 mg capsules) in 24 healthy
`
`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`subjects under fasting condition. After a single dose administration of 1.5 g TRADENAME, the peak
`‘ plasma concentrations of mesalamine were observed at about 4 hours post dose and the half-life was
`about 9 hours. The mean phannacokinetic parameters of mesalamine and N-Ac-S-ASA are in Table
`1.
`
`Table 1: Mean (iSD) plasma pharmacokinetic parameters of mesalamine (5—ASA) and N-Ac—5—
`ASA after a single dose and multiple dose administration of 1.5 g TADE NAME in Healthy
`Volunteers
`
`Mesalamine (S-ASA)
`AUCo—24 (Hg*h/mL)
`
`AUCo.inf(ug*h/mL)
`
`Cmax(ug/mL)
`
`Tmax (h) a
`t-,,(h)
`
`N—Ac—S-ASA
`
`AUCo-24 (11g*h/mL)
`
`AUCo_inf(pg*h/mL)
`
`Cmax(l1g/In-L)
`
`max)“
`ty,(h)
`
`Single Dose
`(%CV)
`(n=24)
`
`10.96 :1: 4.52
`(41.3)
`13.57 i: 5.44
`(39.8)
`2.133: 1.10
`(51.4)
`4 (2, 16)
`9.2:|:7.l
`159.3)
`
`25.55 i 5.52
`(21.6)(
`50.62i 23.06
`(45.6)
`2.78 :1: 0.85
`(30.5)
`4 (4, 12)
`12.43: 10.8
`(1 1.6)
`
`Multiple Dosesb
`(%CV)
`(n=24)
`
`16.90 $5.70
`(33.7)
`26.60 i 14.82
`(55.7)
`2.72i 1.14
`(41.8)
`4 (2, 8)
`10.1:l:8.l
`(68.5 2
`
`37.00 :1: 8.90
`(24)
`86.06 1:52.48
`(61)
`3.40i 0.90
`(26.3)
`5 (2, 8)
`13.6:t 10.2
`(77.8)
`
`“‘ median (min, max)
`bi 7 days of treatment: Steady-state was achieved on Day 6
`
`' TRADENAME
`received
`subject
`each
`period,
`multiple-dose
`the
`In
`1.5 g every 24 hours (QD) for 7 consecutive days. Steady state was achieved on day 6 and mean
`Cmax was about 22-25% higher for S—ASA and N-Ac-S-ASA at steady state compared to that alter a
`single dose administration. At steady state, moderate increases (1.5—fold and 1.7-fold) in systemic
`exposure (AUCcm) to 5-ASA (47.5% CV) and N-Ac-S-ASA (27.4% CV) were observed when
`compared with a single-dose of TRADE NAME.
`
`In a separate study, after a single-dose of 1.6 g mesalamine granule in sachet (sMG, 2X800mg) under
`fasting condition about 31.6 :1:10.6% (mean d: SD) of the administered dose was systemically
`absorbed based on the mean combined cumulative urinary excretion of mesalamine and N-Ac-S-
`ASA. The metabolite, N-Ac-S-ASA was predominant in urine consisting of 30 % of administered
`dose and approximately 2% was excreted unchanged in urine.
`
`Food eflect
`
`

`

`NDA 22—301 Original
`Review of Clinical Pharmacology
`
`Effect of a high fat meal on absorption of mesalamine was studied in 30 healthy subjects receiving
`1.6 g of MG in sachet (2 x 0.8 g) (Study MPPKlOOZ). Under fed condition, tmax for mesalamine and
`N-Ac-S-ASA was prolonged by 4 and 2 hours, respectively. There was a moderate increase in
`absorption of mesalamine (ll-16% increase in AUC) while Cmax of mesalamine was similar with or
`without food. Nevertheless, overall absorption of administered dose was not affected by a high fat
`meal, based on the combined cumulative urinary excretion of mesalamine and N-Ac-S-ASA.
`Therefore, sMG can be taken without regard to food. Although the food effect study was conducted
`using sMG, the food effect study results can be extended to the TRADENAME (eMG) since the
`release-controlling portion of the products remains the same and the equivalence between sMG and
`TRADENAME was demonstrated.
`In addition, the phase 3 trials conducted with eMG, the drug was
`taken without regard to food intake. Therefore TRADENAME can be taken without regard to food
`intake.
`
`Mesalamine 5~ASA and N-Ac-S-ASA did not inhibit the ma'or CYP en mes evaluated.
`
`The final study report of an in vitro drug interaction study (XT0055039) was submitted previously as
`NDA 20-610, SLR017 dated May 3, 2007 and reviewed by Dr. Abimbola Adelowale of the Division
`of Clinical Pharmacology 3. The concentration range studied in the in vitro study e.g. 0.1-100 pM
`sufficiently covered the mean Cmax for S-ASA (17 uM) and N-Ac-S-ASA (35 pM) at steady state
`with TRADE NAME. There was no significant inhibition of CYP enzymes (CyplA2, Cyp2C9,
`Cyp2Cl9, Cyp2D6, and Cyp3A4/5) by S-ASA and its major metabolite N-Ac-S-ASA. Therefore, the
`study report XT0055039 was not further reviewed this time.
`
`Relative Bioavailabilifl
`
`The bioavailability of S-AS and N-Ac-S-ASA after 4 day administration of sMG by dosage regimen
`of 0.8 g BID was compared to the dosage regimen of 1.6 g QD.
`It was also compared to AUC and
`Cmax after administration of Asacol 0.8 g (2 x 400 mg) BID for 4 days in 30 healthy subjects (Study
`MPPKlOOl).
`
`The systemic exposure to 5-ASA and N—Ac-S-ASA was higher after sMG 0.8 g BID and 1.6 g QD
`than Asacol 0.8 g BID. Higher variability (72~128% CV) was observed in PK parameters after
`Asacol treatment compared to after the sMG treatments (33—55%). The median trnax of S-ASA and
`N-Ac-S-ASA after sMG QD was about 3 hours and it was about 16 hours for sMG BID and Asacol
`BID indicating a carryover effect from the first dose. The mean AUC and Cmax of S-ASA and N-
`Ac-S-ASA alter sMG 0.8g BID and sMG 1.6 QD treatments were higher than those for Asacol 0.8 g
`BID treatment. The sponsor concluded that PK parameters for Asacol treatment were unreliable
`because intact or partially intact tablets were recovered from stool samples of 50% of subjects afier
`Asacol treatment. Because the safety and efficacy of 1.5g eMG once daily dosing were evaluated in
`two placebo—controlled phase 3 clinical
`trials and one open-label
`long-term safety trial,
`the
`comparison ofBA of TRADENAME to Asacol 400 mg tablet is not considered critical to this NDA.
`
`The ratio of mean Cmax afier sMG 0.8 g BID to after sMG 1.6g QD was 153% for 5-ASA and 118%
`for N-Ac-S-ASA while the AUC was similar between two treatments. However, attainment of the
`steady-state is uncertain as sMG was administered once daily or twice daily for 4 days only.
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`Table 2*. Mean (:|:SD) PK parameters after administration of sMG and ASACOL for 4 days.
`
`Treatment C
`
`sMG 1600 mg QD
`n=28
`
`
`
`
`
`C/B Ratio
`
`(90% CI)
`
`
`
`Treatment BID
`
`Asacol 800 mg BID
`N=28
`
`
`
`
`
`Treatment B
`
`sMG 800 mg BID
`n=28
`
`Cmax (Hg/H114)
`
`1.82 :1: 0.71
`3.61 d: 1.23
`
`AUC (ug*h/mL)
`
`
`
`
`
`
`
`
`
`5-ASA
`N-Ac-S—ASA
`
`1.06 :t 1.37
`2.34 i 1.80
`
`3.04 :1: 1.67
`4.50:1: 1.82
`
`153 113, 208
`118 98,143)
`
`5-ASA
`N-Ac-S-ASA
`
`8.43 i750
`30.72 i 22.25
`
`14.84 :I: 5.50
`46.371: 15.43
`
`'
`
`14.76 5: 6.49
`45.85 :1: 19.71
`
`96 (76, 121)
`93 78, 112
`
`Tmax (h)
`
`3(2, 16) —
`160), 24)
`16(0,24)
`5—ASA
`
`
`3 2,24 -
`16(0, 24
`16 0,24
`N—Ac-S-ASA
`*Modified from the sponsor’s table to correct units for Cmax and AUC
`
`Dose selection rationale for 2.hose 3 program
`The sponsor selected the daily dose of 1.5g for phase 3 trial because the daily dose 1.5 g is close to
`the approved doses for other mesalamine products for maintenance of remission of Ulcerative colitis
`e.g. 1.6 g daily dose (0.8 g, BID) for Asacol 400 mg. There was no phase 2 dose-ranging trial
`conducted. After 4 days of treatment, Cmax was higher for the regimen 1.6 g sMG QD than 0.8g
`sMG BID regimen while AUC was similar.
`Because mesalamine is believed to act locally, the
`higher systemic exposure to 5-ASA and N-Ac—S-ASA is generally not favored from a safety
`standpoint. Nonetheless, because safety and efficacy of the once daily regimen of 1.5 g mesalamine
`was evaluated in two placebo-controlled pivotal phase 3 trials, the acceptability of the safety profiles
`of the proposed dosing regimen will be based on the phase 3 results.
`
`,2
`
`Question—Based Review
`
`2.1
`
`General Attributes of the drug
`
`2.1.1 What pertinent regulatory background or history contributes to the current assessment of the
`clinical pharmacology and biopharrnaceutics of this drug?
`
`NDA 22~301 was submitted via a 505(b)(2) pathway. The clinical safety and efficacy of the
`TRADENAME was supported by three phase 3 trials conducted with TRADENAME. The sponsor
`intended to reference non-clinical findings from the reference product, Asacol 400 mg.
`The study report MPPK1003 was submitted at month 5 into the review cycle (June 13, 2008) as an
`amendment to provide adequate single and multiple dose PK information for TRADE NAME. The
`deficiency of the study MPPK1003 at the NDA submission was not considered a filing issue. The
`division agreed to review the study at the filing because the study appeared to be designed better to
`previde adequate PK information than other studies with weakness in study deisng e.g. insufficient
`PK sampling duration (MPPK1002) and uncertainty of attainment of steady-state (MPPKIOOI).
`
`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`2.1.2 What are the highlights of the chemistry and physical—chemical properties of the drug
`substance, and the formulation of the drug product as they relate to clinical pharmacology and
`biopharmaceutics review?
`
`Each capsule contains 0.375 g of mesalamine USP (S-aminosalicylic acid, 5-ASA), an anti—
`inflammatory drug. The formulation is presented in Table 3. The structural formula of mesalamine
`is:
`
`HN
`2
`
`OH
`
`OH
`
`Molecular Weight: 153.135
`Molecular Formula: C7H7N03
`
`Formulation
`
`l“
`
`b(4)
`
`Each eMG capsule is produced by encapsulating, in a hard gelatin size “00”. capsule shell, a quantity
`of mesalamine granules to provide 375 mg of active ingredient (mesalamine) per capsule.
`
`The mesalamine granules (MG) in TRADE NAME were modified from the original mesalamine
`granule formulation (FMG) developed by Dr. Falk Pharma in Germany (Table 3). The sponsor
`submitted the final reports of studies SAG-l6/BIO, SAG-4/BIO, SAG—ZS/BIO and SAG-l9/BIO
`conducted using FMG. The studies were conducted mostly by different dosage regimens from the
`except for SAG-25/BIO. Two products were comparable in a comparative in vitro dissolution test
`and met 123 50 criteria (Please, see CMC review by Dr. Gene W. Holbert). However, because of
`level 3 manufacturing site change for modified release products, an in vivo BE study was required.
`Therefore, studies conducted using FMG product are considered only supportive.
`
`2.1.3 What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`The mechanism of action of 5-ASA is unknown, but appears to be local to the intestinal mucosa
`rather than systemic. Mucosal production of arachidonic acid metabolites, both through the
`cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes
`and hydroxyeicosatetraenoic acids, is increased in patients with chronic inflammatory bowel disease,
`and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid
`metabolites.
`
`TRADENAME is proposed for the indication of maintenance of remission of ulcerative colitis in
`patients 18 years of age and older.
`
`2.1.4 What are the proposed dosage(s) and route(s) of administration?
`
`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`Each TRADE NAME capsule contains 0.375 g of delayed—release granules for oral administration.
`The proposed dosage regimen is to take four capsules of TRADENAME (1.5g, 4X0.375g) once daily
`with or without food.
`
`The single-dose and multiple dose PK study, Study MPPK1003 was conducted using TRADE NAME
`(eMG) under consistent condition as the proposed dosage regimen. On the other hand, studies
`MPPKIOOI and MPPK 1002 were conducted using mesalamine granules in sachet (sMG) at 1.6 g
`(2X0.8g). The same mesalamine granules were used for sMG and TRADE NAME and the release of
`mesalamine from two products 'were comparable meeting f2: 50 criteria.
`
`2.2
`
`General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to support
`dosing or claims?
`'
`
`Reviewer’s comments: The bioanalytical assay method used for plasma concentrations of
`mesalamine and N-Ac-S-ASA in MPPKIOOI and MPPK1002 was different from the method used in
`MPPK1003.
`
`Study MPPK1001 was a randomized, single center, open-label, crossover trial in 30 healthy subjects
`that compared the pharmacokinetics, urinary excretion and fecal excretion of mesalamine and N-Ac—
`S-ASA after oral administration of mesalamine granules (0.8 g BID or l.6g (2x800mg) QD for 4
`days) to that from Asacol (2x 800 mg, QD) tablets.
`
`two-
`two-period,
`two-treatment,
`randomized, balanced,
`Study MPPK1002 was an open-label,
`sequence, cross-over study of a single dose of mesalamine granules (1.6 g, 2 x 800 mg) administered
`orally following an overnight fast and following ingestion of a high-fat meal (breakfast). Plasma,
`urine, and feces were collected to assess the effect of a high-fat meal on the pharmacokinetics of
`mesalamine and N-Ac-S-ASA.
`
`Study MPPK1003 was open-label, single— and multiple-dose study of the relative bioavailability and
`phannacokinetics of eMG in healthy volunteers. A total of 24 subjects were enrolled into this study.
`Each subject received a single dose of mesalamine administered as 1.5 g eMG (4 x 375 mg) followed
`by 96 hours of blood sampling for pharmacokinetic analyses. After a 7-day washout period, each
`subject received multiple doses of mesalamine, administered as 1.5 g eMG (4 x 375 mg) every 24
`hours (QD) for 7 consecutive days.
`’
`
`single-center
`Study SAG-16/BIO was a randomized, observer—blind, crossover, single-dose,
`pharmacoscintigraphy study in 14 healthy male subjects that evaluated the transport, site of release,
`and absorption of mesalamine from mesalamine granules and the tablet formulation.
`In this study,
`healthy male volunteers ingested a single 500-mg mesalamine granules dose containing 2 mg
`15$m203 (mean 1.4 MBq per dose).
`(Note: The samarium oxide is not absorbed by the
`gastrointestinal tract.) Scintigraphy was used to monitor transit and release of drug in the GI tract.
`
`Studies MPUC3003 and MPUC3004 were similarly designed Phase 3, randomized, double-blind,
`placebo-controlled, multicenter studies to compare the once daily (QD) dosing of eMG 1.5 g versus
`placebo afler 6 months of treatment in the maintenance of remission of ulcerative colitis (UC), and.
`the safety of eMG at this dose regimen and duration.
`
`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`long-tenn safety and tolerability study in subjects who
`Study MPUC3005 was an open—label
`successfully participated in MPUC3003 or MPUC3004 or in males and non—pregnant females in
`remission for UC for > 1 to _<_ 12 months.
`Table 3. Formulation Comparison: Loose Mesalamine Granules (Dr. Falk Pharma formulation,
`FMG) vs. Encapsulated Mesalamine Granules (MG)
`
`
`% Composition (wlw)
`Dr. Folk Pharma
`Formulation
`
`Salix Formulation
`
`Component
`Active Ingredient
`
`
`
`M4)
`
`N4)
`
`
`
`
`
`Colloidal silicone dioxide
`Magnesium steamte
`
`Microcwstalline cellulose
`
`'simethioonc emulsion "
`
`
`f Polymhylacrylnter
`
`melhylmelhacrviate‘l -' nonoxynni
`
`100 dis n ersion
`
`
`.mm..y¢_\
`
`
`
`rfiypgomellose i
`..__.__-.
`
`% Com sifion (wlw)
`Dr. Folk Pharma
`Formulation
`
`Component
`~___._.—-——-v
`
`Salix Formulation
`
`VPolv(mefliacrvlic acid, 7
`
`/
`
`Magnesium stearate
`Talc
`Titanium dioxide
`'I‘riethyl citrate
`- ~ -
`n
`
`W.. ..__.- __.. _» °
`Hypromellose (
`
`Citric acid. anhvdrous
`
`Vanillaflavoring
`Hypromellose-r
`
`,_
`-——"
`
`Encapsulation
`
`Lightblue. opaque “00" hard gelatin capsule shell _—
`
`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`2.2.2 What is the basis for selecting the response endpoints, i.e., clinical or surrogate endpoints and
`how are they measured in clinical studies?
`
`the primary ' efficacy endpoint was the proportion of
`For studies MPUC3003 and MPUC3004,
`subjects who remained relapse- free at Month 6/EOS. Relapse (or treatment failure) Was defined as a
`rectal bleeding score. of 1 or more and a mucosa] appearance score of 2 or more as described in the
`revised Sutherland Disease Activity Index (BM) in Table 4.
`
`Table 4. Summary of Revised Sutherland Disease Activity Index for Studies MPUC3003 and
`MPUC3004
`'
`
`Stool fr
`equ
`
`enc
`y
`
`Rectal bleeding
`
`
`
`Mucosal appearance ‘
`
`
`
`
`
`Scale Ratings
`O= Nonml
`
`l =
`l to 2 stools/day more than normal
`2 =
`3 to 4 stools/day more than normal
`3 =
`>4 stools/day more than normal
`— None
`
`Streaks ofblood
`1 =
`— Obvious blood
`
`OWNoIlll
`
`- Mostly blood
`—
`Intact mucosa with preserved or distorted vessels
`I
`—-
`Erytherna, decreased vascular pattern, granularity, no mucosal
`. hemorrhage
`'
`2 = Mucosal hemorrhage without blood in the lumen or gross
`ulceration, marked erythema, absent vascular pattern, small ulcers
`3 = Blood in lumen, gross ulceration, exudates
`0 = Normal
`
`
`
`
`
`Severe
`
`
`Physician ’3 rating of
`disease activity
`
`MAXIMUM SCORE
`
` 2= Moderate
`3=
`
`
`
`
`
`Source: Sutherland, et al., 1987
`a For studies MPUC3003 and MPUCS 04. the Sutherland DAl (Sutherland et a1. 1987) was revised to
`remove the term “mild friability" from the mucosa! appearance score of l and the term “moderate
`friability" from the mucosa! appearance score of 2.
`
`2.2.3 Are the active moieties in the plasma, urine and feces appropriately identified and measured
`to assess pharmacokinetic parameters?
`
`Mesalamine and a major metabolite, N-Ac-S-ASA were measured in plasma, urine and feces.
`Because mesalamine is thought to act locally, the systemic exposure of mesalamine and N—Ac-S-ASA
`is considered most relevant to the safety, of the treatment. The measurement of N—Ac-S-ASA has
`been conducted since AUC of N—Ac-S-ASA was greater than mesalamine e.g. 2 folds higher than
`mesalamine after multiple doses.
`In addition, as the absorbed dose is primarily‘excreted as N—Ac-S-
`ASA in urine, N—Ac-S—ASA has been considered potentially relevant
`to kidney toxicity of
`mesalamine.
`
`

`

`NDA 22-30] Original
`Review of Clinical Pharmacology
`
`The interpretation of fecal samples was complicated due to incapability of differentiate between .
`released and unreleased mesalamine and formation of N-Ac-S-ASA from mesalamine in feces during
`sample process was not evaluated.
`'
`
`There was no phase 2 dose-ranging study conducted and the systemic exposure of mesalamine and its
`major metabolite N-Ac-S-ASA was not assessed in patients.
`
`2.2.5
`
`Pharmacokinetic Characteristics
`
`The pharmacokinetics of mesalamine (S-ASA) and its metabolite, N-Ac-S-ASA, were studied after a
`single dose and multiple oral doses of 1.5 g TRADE NAME (QD, 4 x 375 mg capsules) in a
`crossover study in healthy subjects under fasting. After a single dose administration of 1.5 g
`TRADENAME, the peak plasma concentrations of mesalamine were observed at about 4 hours post
`dose and the half-life was about 9 hours (Figure 2). The mean pharmacokinetic parameters of
`mesalamine and N-Ac-S-ASA are in Table 5.
`
`Figure 2. Mean (iSD) Concentration-Time Profiles of S-ASA and N-Ac-S-ASA after single dose
`and multiple doses of 1.5 g TRADE NAME
`
`‘ (A) S-ASA
`
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`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
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`Table 5: Mean (iSD) plasma phai‘macokinetic parameters of mesalamine (5-ASA) and N—Ac—S-
`ASA after a single dose and multiple dose administration of 1.5 g TADE NAME in Healthy
`Volunteers
`
`-
`
`Mesalamine (S-ASA)
`
`, Number of subjects
`AUCo.24 (ug*h/mL)
`
`AUCo.inr(Hg*h/mL)
`
`Cmax (pg/mL)
`
`Tmax (h) a
`t-,,(h)
`
`.
`
`N-Ac-S-ASA
`
`AUCo-24 (Ham/m1.)
`
`AUCo-inr(ug*h/mL)
`
`Cmax (pg/mL)
`
`Tmax (h)“
`t-,, (h)
`
`Single Dose
`(CV%)
`
`Multiple Doses”
`(CV%)
`
`24
`
`24
`
`10.96 i 4.52
`(41.3)
`13.57 i 5.44
`(39.8)
`2.13 d: 1.10
`(51.4)
`4 (2, 16)
`92:127.]
`(59.3)
`
`25.55 i 5.52
`(21 .6)(
`50.621: 23.06
`(45.6)
`2.78 d: 0.85
`(30.5)
`4 (4, 12)
`12.4 :1: 10.8
`g 1 1.6)
`
`16.90 15.70
`(33.7)
`26.60 a: 14.82
`(55.7)
`2.72 :1: 1.14
`(41.8)
`4 (2; 8)
`lO.l:1:8.]
`(68.5)
`»
`
`37.00 :1: 8.90
`(24)
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`(61)
`3.403: 0.90
`(26.3)
`5 (2, 8)
`13.6:1: 10.2
`(77.8)
`
`a: median (min, max)
`b‘ 7 days of treatment: Steady-state was achieved on Day 6
`
`11
`
`

`

`NDA 22-301 Original
`' Review of Clinical Pharmacology
`
`TRADENAME
`g
`1.5
`received
`subject
`each
`period,
`multiple-dose,
`the
`In
`every 24 hours (QD) for 7 consecutive days. Steady state was achieved on day 6 and mean Cmax
`was about 22—25% higher for 5-ASA and N—Ac-S-ASA at steady state compared to that after a single
`dose administration. At steady state, moderate increases (LS-fold and 1.7-fold) in systemic exposure
`(AUCM4) to S—ASA and N-Ac-S—ASA were observed when compared with a single—dose of TRADE
`NAME. The ratio of AUC24 afler multiple doses to AUC inf after a single—dose was 1.23 for S-ASA
`and 0.78 for N—Ac-S-ASA. While modest variability (40—45 % CV) was associated with AUC M of 5-
`ASA and N-Ac-S-ASA, it was suggested that it may be a result of slightly lower rate of metabolism to
`N-Ac-S-ASA following repeated oral administration of TRADENAME.
`
`.
`
`After a single-dose of 1.6 g mesalamine granule administration (2X800mg) under fasting condition
`about 31.6 i10.6% of the administered dose was systemically absorbed based on the combined
`cumulative urinary excretion of mesalamine and N-Ac—S—ASA collected over 96 hours post—dose
`(Table 6). Of the administered dose, approximately 2% was excreted unchanged in urine and 29%
`was excreted as N-Ac-S-ASA.
`
`Table 6. Percentage of the administered dose (1.6g expressed as mmols of 5-ASA) for
`cumulative urinary excretion
`
`S-ASA
`
`
`
`
`N-Ac-S-ASA
`
`S-ASA lus N-Ac-S-ASA
`
`
`
`
`
`Fasted (N=30)
`.
`Fed (n=30)
`% administered dose
`% administered dose
`
`
`1.95i 1.72 %CV 88 4
`2.47 i 2.16 %CV 87.6
`
`
`
`
`29.62 :1: 9 57 (%CV 32.3)
`31.56:!: 10.55 (%CV 33.4)
`
`29.48 :I: 11.65 (%CV 39.5
`3 1.95:1: 13.00 (%CV 40.6)
`
`In study BIO/SAC—16, the FMG was compared with another mesalamine tablet for intestinal transit
`and the extent of absorption while in a target region of intestine e.g. ileo-caecal region based on
`scintigraphic imaging and partial AUC. The sponsor proposes a labeling claim of “Approximately
`80% of an administered oral dose of mesalamine is estimated to be available in the colon, sigmoid,
`and rectum when dosed as mesalamine granules.”
`
`In addition, the quantitative estimation
`The study was qualitative in nature to compare two products.
`of local availability of mesalamine in a specific region is limited due to incapability of differentiation
`of released mesalamine and unreleased mesalamine from the granules or disintegrated versus intact
`mesalamine granules by scintigraphic analysis.
`In addition, the absorption while in the region may
`not be paralleled with the availability of released mesalamine in the target region of intestine due to a
`limited absorption at the target region of intestine. Therefore, the data provided by this study is
`considered insufficient to support the quantitative estimation of local availability of administered
`mesalamine.
`
`In addition, the FMG was manufactured in Europe while TRADENAME was manufactured in the
`US. The sponsor conducted an in vitro comparative dissolution study and the comparison met the
`f2>50 criteria for equivalence. However, because this manufacturing site change is considered level
`3 change, an in vivo BE study is normally required for adequate and sufficient bridging. Therefore, it
`is unknown how relevant this information to TRADENAME.
`
`2.4
`
`Extrinsic Factors
`
`12
`
`

`

`' NDA 22-301 Original
`Review of Clinical Pharmacology
`
`2.4.1 Does mesalamine (S-ASA) and N—Ac-S—ASA have in vivo drug interaction potential?
`
`The in—vitro enzyme inhibition study (Study XT005039) was conducted to evaluate inhibitory effects
`of 5—ASA and N-Ac-5-ASA, on human cytochrome P450 enzymes. The study report was previously
`submitted as supplement to NDA 20-610 (SLR 017 dated May 03, 2007) and reviewed by Dr.
`Abimbola Adebowale of Division of Clinical Pharmacology3. The study results are reflected in the
`current approved Colazal® label. As such the detailed review is referred to the previous review.
`Below is a brief summary from the original review of Study XT005039 by Dr. Adebowale.
`
`inhibitors of CYP activity, human liver
`Briefly, to evaluate 5-ASA and N-Ac-S-ASA' as direct
`microsomes (at < 0.1 mg/mL) from a pool of sixteen individuals were incubated with marker
`substrates, at concentrations approximately equal to their apparent Km, in the presence or absence of
`5-ASA, and N-Ac-S-ASA. The target concentrations ranged from 0.1 to 100 uM. In addition, 5-ASA,
`and N-Ac-5-ASA were evaluated for their ability to function as metabolism-dependent inhibitors at
`the same concentrations mentioned above, in which case they were pre-incubated with human liver
`microsomes (at < 0.1 mg/mL) and an NADPH—generating system for 30-minutes to allow for the
`generation of metabolites or intermediates that might
`inhibit CYP activity. Known direct and
`metabolism-dependent inhibitors of CYP enzymes were included as positive controls.
`
`Under the experimental conditions examined, there was no evidence of direct inhibition of CYP 1A2,
`CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 (as measured by testosterone 6B-
`hydroxylation and midazolam 1' hydroxylation) by 5-ASA, and N-Ac—S-ASA, as the ICSO
`values for these enzymes were greater than the highest concentration examined (100 uM). In
`addition, 5-ASA, and N-Ac—S—ASA did not appear to be metabolism-dependent inhibitors of any of
`the CYP enzymes that were examined, as an increase in inhibition was not observed upon pre—
`incubation. The 1C5 0 values for direct and metabolism-dependent inhibition
`were reported as > 100 M for all CYP enzymes evaluated.
`
`Below is excerpt from the section 7 drug interactions in the Colazal® label.
`
`“7 DRUG INTERACTIONS
`
`In an in vitro study using human liver microsomes, balsalazz'de and its metabolites [5-
`aminosalz‘cylic
`acid (5-ASA), N-acetyl—5-aminosalicylic acid (N-Ac-S-ASA),
`4-
`aminobenzoyl—j37alanz'ne (4-ABA) and N-acetyl—4-aminobenzoyl— fl —alanine (N-Ac-4—
`ABA)] were not shown to inhibit
`the major CYP enzymes evaluated (CYP1A2,
`CYP2C9,CYP2C19, CYP2D6, and CYP3A4/5). Therefore, balsalazide and its
`metabolites are not expected to inhibit the metabolism of other drugs which are
`substrates ofCYP1A2,CYP2C9, CYP2C19, CYP2D6, or CYP3A4/ . ”
`
`i 2.5
`
`General Biopharmaceutics
`
`2.5.3 What is the effect of food on the bioavailability (BA) of the drug from the dosage form?
`What dosing recommendation should be made, if any, regarding administration of the product
`in relation to meals or meal types?
`
`Food effect
`Effect of a high fat meal on absorption of mesalamine granules in sachet (sMG) was studied in 30
`healthy subjects received 1.6 g of sMG (2 x 0.8 g). Under fed condition, tmx for mesalamine and
`
`13
`
`

`

`NDA 22-301 Original
`Review of Clinical Pharmacology
`
`N—Ac—S-ASA was prolonged by 4 and 2 hours, respectively and a moderate increase in absorption of
`mesalamine was observed (16% increase in AUCm) But Cmax of mesalamine was similar with or
`without food. The mean half-lives of mesalamine were estimated to be 5.49 hours with food and 8.42
`
`hours without food; while the mean N-Ac-S—ASA half-live were estimated 10.05 hours with food and
`12