Research Report
`
`Bioavailability profile of
`Õ
`Õ
`MMX
`extended-
`Uceris
`release tablets compared
`Õ
`EC capsules
`with Entocort
`in healthy volunteers
`
`Andrew Nicholls,1 Rau´ l Harris-Collazo,2
`Michael Huang,2 Yun Hardiman,2
`Richard Jones3 and Luigi Moro3
`
`Journal of International Medical Research
`0(0) 1–9
`! The Author(s) 2013
`Reprints and permissions:
`sagepub.co.uk/journalsPermissions.nav
`DOI: 10.1177/0300060513476588
`imr.sagepub.com
`
`Õ
`
`Abstract
`formulation of
`Objective: To compare the pharmacokinetics of the extended-release MMX
`Õ
`Õ
`) with that of Entocort
`EC, an extended (controlled ileal) release
`budesonide (Uceris
`formulation of budesonide.
`Methods: Using an open-label, randomized, three-period crossover, Latin square design, healthy
`Õ
`Õ
`Õ
`, 9 mg Uceris
`or 9 mg Entocort
`male or female volunteers received single doses of 6 mg Uceris
`EC. Standard pharmacokinetic parameters were assessed.
`Õ
`Results: The study included 12 subjects. The 9 mg Uceris
`EC formulations
`and 9 mg Entocort
`Õ
`had a
`had comparable area under the concentration–time curve (AUC) data, but 9 mg Uceris
`notably longer time to first appearance in plasma (median Tlag, 6 h versus 1 h, respectively), and a
`delayed time to maximum concentration (median Tmax, 15 h versus 5 h, respectively) compared
`Õ
`Õ
`Õ
`/Entocort
`EC) was 91%
`EC. The ratio of log-transformed AUC0–last (Uceris
`with 9 mg Entocort
`(90% confidence interval [CI] 77%, 108%) and the corresponding maximum concentration ratio
`was 79% (90% CI 63%, 100%).
`Conclusion: Uceris was associated with a similar extent (AUC) of systemic exposure to
`budesonide compared with that following Entocort. However, for Uceris, the pharmacokinetic
`profile was delayed, a pattern consistent with greater colonic delivery of the active substance.
`
`Õ
`
`Keywords
`Bioavailability, bioequivalence, budesonide, ulcerative colitis
`
`Date received: 28 November 2012; accepted: 3 December 2012
`
`1Pharmaceutical Consulting, Encinitas, CA, USA
`2Santarus Inc (Medical Affairs, Clinical Development,
`Biostatistics), San Diego, CA, USA
`3Cosmo Technologies Ltd (Clinical Development), Ireland
`
`Corresponding author:
`Dr Andrew Nicholls, Pharmaceutical Consulting, 961
`Hermes Avenue, Encinitas, CA 92024, USA.
`Email: andrew.nicholls@sbcglobal.net
`
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`2
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`Journal of International Medical Research 0(0)
`
`Introduction
`
`Conventional treatments for mild-to-mod-
`erate ulcerative colitis (UC) include 5-ami-
`nosalicylates
`and
`systemic
`glucocorticoids.1–3 Nonsystemic (or locally
`acting) glucocorticoid therapies directly tar-
`geting the inflamed mucosa in inflammatory
`bowel disease have the potential for consid-
`erable safety advantages over comparable
`systemic treatments. Budesonide is a potent
`glucocorticoid with low systemic bioavail-
`ability (10–15%) due to extensive presyste-
`mic inactivation in which the drug is
`metabolized via the
`cytochrome P450
`(CYP) enzyme CYP3A4 into two principle
`6b-hydroxybudesonide
`metabolites,
`and
`16a-hydroxyprednisolone.4,5 These metab-
`olites have negligible glucocorticoid activity
`compared with the parent drug.4 As a
`consequence, budesonide has only modest
`effects
`on
`the
`hypothalamic–pituit-
`ary–adrenal axis.6,7 As an example, a
`rectally-administered budesonide
`enema
`was found to have comparable efficacy to a
`rectally-administered prednisolone enema in
`UC, but was associated with significantly
`less plasma cortisol suppression.8
`Oral budesonide, administered as a plain
`formulation, is completely absorbed high in
`the gastrointestinal (GI) tract, making this
`formulation unsuitable for the treatment of
`UC, which requires delivery of active drug
`distally to the entire colon for optimal
`Õ
`EC (Astra
`therapeutic effect. Entocort
`Zeneca, London, UK) is a budesonide for-
`mulation containing granules
`that are
`coated to prevent dissolution in gastric pH.
`This formulation releases budesonide as it
`passes
`through
`the
`small
`intestine
`(pH > 5.5), delivering the steroid to the
`distal ileum and allowing treatment of ter-
`minal ileal or right-sided colonic Crohn‘s
`disease.5,9,10 However,
`in contrast
`to
`Crohn’s disease, UC typically involves the
`colon (and usually the left colon):11 a pat-
`tern of disease that requires more distal
`
`Õ
`
`distribution of budesonide than can be
`Õ
`.
`achieved by Entocort EC
`multimatrix
`An
`extended-release
`formulation of
`)
`system tablet
`(MMX
`Õ
`; Santarus, San Diego,
`budesonide (Uceris
`CA, USA) has been developed, with the
`active ingredient embedded in a sequence of
`lipophilic and amphiphilic matrices sur-
`rounded by hydrophilic polymers. In con-
`Õ
`Õ
`EC, Uceris
`is covered by
`trast to Entocort
`a gastroresistant methacrylic acid copoly-
`mer coating that dissolves in intestinal fluids
`with pH 7. Once in the lower intestinal
`tract, the coating dissolves, and the intes-
`tinal fluid comes into contact with the
`hydrophilic matrix polymers, which swell
`to form a viscous gel matrix. As the gel
`matrix dissolves, budesonide is gradually
`released from the internal lipophilic matrices
`in a controlled fashion.12
`The GI transit and pharmacokinetics of
`Õ
`have been evaluated using g-scinti-
`Uceris
`graphy of 153Sm-labelled tablets containing
`9 mg of budesonide.13 The appearance of
`budesonide in the systemic circulation was
`almost exclusively (96%) associated with the
`absorption of the dose in the colon.
`The efficacy of the once-daily tablet for-
`Õ
`in patients with active
`mulation of Uceris
`mild-to-moderate UC has been evaluated in
`the COlonic RElease budesonide (CORE) I
`and CORE II studies.14,15 These similarly
`designed studies were randomized, double-
`blind, double-dummy, placebo-controlled
`trials, using combined clinical and endo-
`scopic remission at 8 weeks as the primary
`endpoint. Pooled analyses of the CORE I
`and CORE II studies demonstrated that the
`remission rates for patients treated with
`Õ
`Õ
`and 6 mg Uceris
`once daily
`9 mg Uceris
`17.7% (P¼ 0.0002)
`was
`and
`10.9%
`(P¼ 0.0692), respectively, compared with
`6.2% for placebo.16 In the CORE I study,
`significantly higher rates of symptom reso-
`lution were achieved in patients treated with
`Õ
`Õ
`(28.5%) and 6 mg Uceris
`9 mg Uceris
`(28.9%)
`versus
`placebo
`(16.5%;
`
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`Nicholls et al.
`
`3
`
`P < 0.05).14 Similarly, in the CORE II study,
`significantly higher rates of symptom reso-
`lution were achieved in patients receiving
`Õ
`(23.9%)
`versus placebo
`9 mg Uceris
`(11.2%; P < 0.05), but not in patients trea-
`Õ
`(13.8%).15
`ted with 6 mg Uceris
`The objective of the current study was to
`compare the pharmacokinetics of two doses
`Õ
`(6 and 9 mg) of the extended-release Uceris
`formulation of budesonide with that of 9 mg
`3 3 mg
`Õ
`EC (supplied
`as
`Entocort
`capsules).
`
`Patients and methods
`Study design
`
`open-label,
`single-center,
`a
`This was
`single-dose, phase 1, randomized 3-period
`crossover
`study designed to describe
`the pharmacokinetics of a new extended-
`release formulation of budesonide using
`Õ
`Õ
`technology
`(Uceris
`).
`the MMX
`Randomization followed a Latin square
`design ensuring balance (within sex) for
`sequence. Pharmacokinetics data from this
`formulation were to be contrasted with data
`from controlled ileal release budesonide
`provided as 3 3 mg capsules (Entocort
`Õ
`EC). The study also included an evaluation
`Õ
`.
`of the pharmacokinetics of 6 mg Uceris
`This phase 1 study was conducted by
`Cross Research SA (principal investigator:
`Antonio Rusca MD FMH, Phase 1 Unit,
`Arzo, Switzerland) between 5 March and 19
`April 2007. It was performed in accordance
`with
`the
`relevant
`guidelines
`of
`the
`Declaration of Helsinki (1964). Study sub-
`jects were informed of the potential benefits
`and risks of study participation, and entered
`the study after providing written informed
`consent. The study protocol, and all the
`other
`relevant
`documentation,
`were
`reviewed and approved by an independent
`Ethics
`Committee
`(Comitato
`Etico
`Cantonale, Canton Ticino) on 16 January
`2007 (reference number: 1863). The Federal
`Health Authorities (Swissmedic) assigned
`
`the reference number 2007DR1050 to the
`study on 27 February 2007.
`
`Study population
`
`Healthy male or female volunteers, aged 18–
`55 years, body mass index (BMI) 18–29 kg/
`m2, were eligible to participate in the study.
`Subjects were recruited from the local popu-
`lation of Arzo, Switzerland; they had no
`history of inflammatory bowel disease or
`other GI disease. Subjects were on normal
`balanced diets (caloric intake between 1600
`and 3500 kcal/day), with no history of medi-
`cation (prescription or over-the-counter) in
`the 2 weeks prior to the study and no history
`of recreational drug use, or excessive alco-
`hol, caffeine, or tobacco consumption. All
`women of childbearing potential used an
`acceptable method of birth control for 1
`month before dosing, and had a negative
`serum pregnancy test at screening. Subjects
`were excluded if they had a history of renal,
`hepatic, GI, cardiovascular,
`respiratory,
`skin, hematologic, endocrine or neurological
`disease or clinically relevant abnormalities
`on physical examination or evaluation of
`laboratory tests including electrocardiogram
`(ECG), biochemistry and hematology.
`
`Procedures
`
`treatments. Study treatments were
`Study
`administered
`under
`fasting
`conditions
`(10 h since previous meal) with a washout
`interval of 5 days between each study
`period. The randomization sequence was
`determined using a computer-generated
`schedule that included two blocks of six
`treatment sequences and was balanced by
`sex. Prior to each study period, subjects were
`admitted to the clinical research laboratory
`(Phase 1 Unit, Cross Research SA, Arzo,
`Switzerland), where they stayed for 36 h
`after dosing. On each admission to the
`laboratory,
`recent medical history was
`reviewed (including use of alcohol, drugs,
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`4
`
`Journal of International Medical Research 0(0)
`
`and concomitant medications). An alcohol
`breath test, urine drug screening, and a urine
`pregnancy test (when applicable) were per-
`formed. During confinement, subjects were
`not permitted to smoke more than five
`cigarettes per day and coffee,
`tea, and
`xanthine-containing products
`(i.e.
`cola,
`chocolate, etc.) were not allowed 72 h prior
`to each drug administration and during
`confinement. Grapefruit and grapefruit
`juice were forbidden 24 h before first drug
`administration until the end of the study.
`Alcohol was forbidden 36 h before each drug
`administration and during confinement.
`Study medication was administered with
`240 ml of water at 08.00 h 1 h under fasting
`conditions. Subjects were instructed to swal-
`low the dose forms (tablets or capsules)
`whole (without chewing).
`
`Blood collection and analysis. Blood samples
`were collected using a cannula placed intra-
`venously. Samples were obtained at the
`following timepoints: prior to dosing (0 h);
`at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18,
`and 20 h postdose; on day 2 at 24, 30, and
`36 h post-dose. Blood samples (8 ml) were
`collected in polypropylene heparinized
`tubes,
`stored on ice, and centrifuged
`
`C for 10 min,
`(2500 g) within 20 min, at 4
`to obtain plasma. Samples were stored at
`20
`
`C until analysis.
`Samples were packed in solid CO2 prior
`to shipping for analysis by Pharmakin
`GmbH, Neu-Ulm, Germany. Plasma bude-
`sonide
`concentrations were determined
`using validated liquid chromatography–
`mass
`spectrometry/mass
`spectrometry
`methods, with a 50 pg/ml
`lower limit of
`quantitation (LLOQ). At LLOQ, inter- and
`intra-assay precision were 4.88% and
`6.35%, respectively. Values below the limit
`of quantification (<50 pg/ml) were not
`plotted; the late appearance of material in
`the systemic circulation was particularly
`evident for the concentration profiles for
`Õ
`. Values below the limit of
`9 mg Uceris
`
`quantification were treated as zero during
`pharmacokinetic analysis. For clarity, indi-
`vidual plasma concentration profiles for
`Õ
`are not presented, to allow
`6 mg Uceris
`direct comparison of dosing with 9 mg
`Õ
`Õ
`and 9 mg Entocort
`EC.
`Uceris
`Pharmacokinetic analysis (noncompart-
`mental
`analysis) was performed with
`Kinetica software, version 4.4 (Thermo
`Electron, Waltham, MA, USA). Maximum
`time to maximum
`concentration (Cmax),
`concentration (Tmax), and the time of first
`appearance (Tlag) were obtained from the
`concentration data. These data were used to
`determine the area under the concentration–
`time curve (AUC), including AUC0–last, and,
`where appropriate, AUC0–1, and half-life
`(t½). Mean transit time (MTT) was calcu-
`lated using the ratio of the first moment of
`the AUC and AUC itself (AUMC/AUC0–
`1). Mean arrival time (MAT) was derived
`relationship, MTT ¼ MRTþ
`from the
`MAT, where MRT indicates mean residence
`time. Since MRT requires
`intravenous
`administration (not done in this study), an
`externally-derived estimate (3.1 h) from a
`previous study was used.17
`
`assessments
`assessments. Safety
`Safety
`included adverse events; physical examin-
`ations and 12-lead ECG examinations,
`which were performed at screening and
`final visit; vital signs performed on day 1 at
`predose (0 h) and at 4 and 16 h postdose, and
`on day 2 at 24 and 36 h post-dose; and
`routine laboratory tests (hematology, blood
`chemistry, urinalysis) performed at screen-
`ing and final visit.
`
`Statistical analyses
`
`This was an exploratory pharmacokinetic
`study. Accordingly, the sample size was
`selected without consideration of formal
`power calculations for testing bioequiva-
`lence, however a sample size of 12 subjects
`was considered sufficient
`to provide a
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`Nicholls et al.
`
`5
`
`pharmacokinetic
`the
`of
`description
`response. A total of 13 subjects were
`enrolled to ensure that 12 subjects com-
`pleted
`the
`study
`procedures.
`Pharmacokinetic analyses were conducted
`for the 12 subjects who completed the study
`(per protocol population). Safety assess-
`ments considered all enrolled subjects.
`Descriptive statistical summaries of the
`pharmacokinetic data, calculations of point
`estimates and confidence intervals for ana-
`lysis of bioequivalence were prepared,
`together with summaries of demographic
`variables and safety data. In keeping with
`the usual approach for bioequivalence stu-
`dies, point estimates and confidence inter-
`vals were provided for AUC and Cmax.
`Other pharmacokinetic parameters were
`not
`formally tested. Statistical analyses
`Õ
`software, ver-
`were performed using SAS
`sion 9.1.2 (SAS Institute, Cary, NC, USA),
`of log-transformed data in analysis of vari-
`ance models appropriate for
`the Latin
`square design of the study.
`
`Results
`
`A total of 20 healthy subjects were screened
`to identify 13 eligible subjects who were
`randomized to a treatment sequence and
`received study drug. One subject withdrew
`for personal reasons (not specified) prior to
`completing study procedures, resulting in 12
`subjects completing the study and compos-
`ing the per protocol population, of which all
`subjects were Caucasian and six (50%) were
`male. Mean SD age was 37 10 years and
`BMI was 23.0 3.1 kg/m2.
`Inspection of individual subject plasma
`drug concentration profiles (Figure 1) shows
`Õ
`was
`that administration of 9 mg Uceris
`associated with a delay in the appearance of
`budesonide in the systemic circulation, with
`the consequence that plasma concentrations
`over the early postdosing interval (0–6 h)
`Õ
`than
`appeared to be lower for 9 mg Uceris
`Õ
`EC. In contrast, plasma
`for 9 mg Entocort
`
`drug concentrations observed 12 h after
`dosing tended to be greater following 9 mg
`Õ
`treatment compared with those
`Uceris
`Õ
`EC treatment
`following 9 mg Entocort
`(Figure 1; Table 1). Median Tlag (the time
`point at which budesonide was first observed
`above the LLOQ) occurred 6 h after dosing
`Õ
`Õ
`and 6 mg Uceris
`but
`for both 9 mg Uceris
`Õ
`only 1 h after dosing with 9 mg Entocort
`EC (Table 1). Mean MAT was longer for
`Õ
`Õ
`and 6 mg Uceris
`compared
`9 mg Uceris
`Õ
`EC (Table 1).
`with 9 mg Entocort
`9 mg
`Systemic
`exposure
`following
`Õ
`administration was comparable
`Uceris
`Õ
`EC.
`with that following 9 mg Entocort
`The ratio of
`the geometric mean Cmax
`Õ
`Õ
`(Uceris
`/Entocort
`EC) was 79%, with a
`90% confidence interval (CI) around this
`estimate of 63–100%. For AUC0–last, the
`comparable ratio was 91% (90% CI 77%,
`108%). Median Tmax was longer for 9 mg
`Õ
`Õ
`and 6 mg Uceris
`compared with
`Uceris
`EC. The mean SD ter-
`Õ
`9 mg Entocort
`minal half-life (where calculable) was at
`7.5 2.9 h (n¼ 11) for 9 mg Uceris
`Õ
`and
`7.7 1.8 h (n¼ 11) for 9 mg Entocort
`Õ
`EC.
`Three subjects experienced adverse events
`during the study, including two events of
`moderate upper respiratory tract infection
`Õ
`Õ
`and 9 mg Entocort
`EC) and
`(6 mg Uceris
`Õ
`one event of mild headache (9 mg Entocort
`EC). Study drug was otherwise well toler-
`ated with no meaningful effects on vital
`signs, ECG, laboratory parameters, or phys-
`ical examination findings.
`
`Discussion
`
`This study showed that the pharmacokinet-
`ics of budesonide following administration
`Õ
`differed from those following
`of Uceris
`Õ
`EC. The pri-
`administration of Entocort
`mary difference between the two budesonide
`formulations was observed in the lag time
`(Tlag), or the time between oral administra-
`tion of the dose form and first appearance of
`budesonide in the systemic circulation.
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`6
`
`Journal of International Medical Research 0(0)
`
`S1
`
`6.0, 13.3
`
`S2
`
`6.4, 18.1
`
`S3
`
`--, 21.5
`
`S4
`
`8.0, 25.0
`
`S5
`
`8.7, 10.8
`
`S6
`
`6.8, 15.2
`
`S7
`
`8.4, 13.5
`
`S8
`
`5.0, 10.4
`
`S9
`
`S10
`
`S11
`
`S12
`
`14.5, 34.4*
`
`9.7, 19.2
`
`8.5, 17.1
`
`11.3, 21.3
`
`Entocort ® EC
`Uceris ® 9mg
`
`4000
`
`3000
`
`2000
`
`1000
`
`4000
`
`3000
`
`2000
`
`1000
`
`4000
`
`3000
`
`2000
`
`1000
`
`Plasma concentration (pg/ml)
`
`0
`
`12
`
`24
`
`36
`
`0
`
`12
`
`24
`36
`0
`Time (h)
`
`12
`
`24
`
`36
`
`0
`
`12
`
`24
`
`36
`
`Figure 1. Systemic budesonide plasma concentration profiles for individual study subjects (S1–S12),
`Õ
`Õ
`following administration of 9 mg Entocort
`EC (orange) or 9 mg Uceris
`(blue). Values below the lower limit
`of quantification (<50 pg/ml) were not plotted, which was particularly evident in early samples collected for
`Õ
`Õ
`Õ
`plasma profiles. Mean arrival times (MATs), for Entocort
`EC and Uceris
`, respectively, are
`the 9 mg Uceris
`provided in the upper right of each profile. For subject S3, the MAT could not be calculated for 9 mg
`Õ
`EC. For subject S9, the asterisk indicates that the value was influenced by a poorly defined
`Entocort
`Õ
`elimination phase for 9 mg Uceris
`.
`
`The study demonstrated that the phar-
`macokinetic parameters describing exposure
`to systemic budesonide were similar follow-
`ing administration of the two dose forms,
`Õ
`Õ
`and Entocort
`EC. In this study,
`Uceris
`
`which was designed with an arbitrary
`number of
`subjects and without prior
`knowledge of pharmacokinetic variability
`Õ
`formu-
`of the test formulations, the Uceris
`lation of budesonide did not
`exhibit
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`Nicholls et al.
`
`Table 1. Pharmacokinetic parameters after administration of a single dose of 6 mg Uceris
`Õ
`EC in 12 healthy study subjects
`9 mg Entocort
`
`Õ
`
`Uceris
`
`tablets
`
`Parameter
`
`6 mg
`
`9 mg
`
`Cmax, pg/ml
`AUC0–36, pg/ml per h
`AUC0–1, pg/ml per h
`t½, h
`MAT, h
`Tmax, h
`Tlag, h
`
`1158.5 (532.4)
`10818.3 (4401.6)
`11533.6 (4738.5)
`6.6 (2.4)
`13.9 (5.7)
`10 (6–24)
`6 (4–10)
`
`1348.8 (958.8)
`13555.9 (7816.9)
`15160.5 (10020.9)
`7.5 (2.9)
`16.9 (4.7)
`15 (6–24)
`6 (4–7)
`
`7
`
`Õ
`
`, 9 mg Uceris
`
`Õ
`
`or
`
`Õ
`9 mg Entocort
`EC capsules
`
`1555.9 (588.0)
`13394.6 (5983.0)
`14057.0 (6378.7)
`7.7 (1.8)
`8.5 (2.7)
`5 (2–6)
`1 (1–4)
`
`Data presented as mean (SD) or median (range).
`Cmax, maximum concentration; AUC, area under the concentration–time curve; t½, half-life; MAT, mean arrival time; Tmax,
`time to maximum concentration; Tlag, time of first appearance.
`
`Õ
`
`EC at the
`bioequivalence with Entocort
`same dose using conventional regulatory
`criteria for equivalence. The point estimate
`for the ratio of log-transformed AUC0–last
`Õ
`Õ
`(Uceris
`/Entocort
`EC) was 91% (90% CI
`77%, 108%). For Cmax, the corresponding
`data were 79% (90% CI 63%, 100%).
`The processes leading to systemic avail-
`ability of budesonide take substantially
`Õ
`compared with
`longer
`for Uceris
`Õ
`EC. The MAT, calculated using
`Entocort
`an external estimate of MRT from another
`study of budesonide, in which the drug was
`given as an intravenous bolus,17 was 16.9 h
`Õ
`Õ
`and 8.5 h for Entocort
`EC.
`for Uceris
`These current data are consistent with the
`different dissolution and release characteris-
`tics of the two formulations of budesonide.
`As expected, the multimatrix structure of the
`Õ
`tablet, which is designed to release
`Uceris
`the active ingredient more distally in the GI
`tract, had an appreciably greater Tlag and
`Tmax, and a somewhat reduced Cmax, with
`an extended ‘tail’ observed in the pharma-
`cokinetic profile, when compared with
`Õ
`EC.
`Entocort
`A high degree of variability in the
`pharmacokinetics of these formulations is
`consistent with the substantial contribution
`that first-pass metabolic processes play in
`
`the appearance of budesonide in the sys-
`temic circulation.13 Single doses of both
`Õ
`Õ
`and Entocort
`EC were well toler-
`Uceris
`ated in this trial.
`The current study was limited by the fact
`that the study was not powered to test
`bioequivalence. Additionally, the pharma-
`cokinetic sample schedule, which involved
`no observations after 36 h post-dose, led to
`difficulties in full characterization of the
`terminal
`phase,
`in
`some
`subjects.
`Application of the results of this study in a
`healthy subject population to patients with
`UC may be limited by differences in GI
`transit, the pH profile in the GI tract, and
`CYP enzyme activity, all of which may
`influence the pharmacokinetics of budeso-
`nide for these formulations.
`The current study provided pharmacoki-
`netic data suggesting that the extended-
`release formulation of budesonide with
`Õ
`Õ
`technology (Uceris
`) undergoes
`MMX
`in vivo dissolution in a more distal region
`Õ
`of the GI tract compared with the Entocort
`EC formulation, which is consistent with the
`release mechanisms of these formulations as
`demonstrated in a previously-conducted
`study.13 This
`g-scintigraphy
`difference
`resulted in a substantially delayed lag time,
`Õ
`compared with
`MAT, and Tmax for Uceris
`
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`Cosmo Ex 2030-p. 7
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`

`8
`
`Journal of International Medical Research 0(0)
`
`Õ
`
`EC. Systemic budesonide expos-
`Entocort
`ure (AUC) and Cmax were comparable for
`Õ
`Õ
`and Entocort
`EC.
`Uceris
`
`Acknowledgements
`
`The authors would like to thank Dr Edward
`Schweizer, MD, Paladin Consulting Group,
`Princeton, NJ, USA for his contributions in
`developing the initial draft of the manuscript.
`Funding for the development of the manuscript
`was provided by Santarus Inc., San Diego, CA,
`USA.
`
`Funding
`
`This study was funded by Cosmo Technologies
`Ltd, Dublin, Ireland.
`
`Declaration of conflicting interest
`
`Dr Andrew Nicholls is a consultant to Santarus
`Inc., San Diego, CA, USA. Drs Yun Hardiman,
`Rau´ l Harris-Collazo and Michael Huang are full-
`time employees of Santarus Inc., San Diego, CA,
`USA. Richard Jones and Dr Luigi Moro are full-
`time employees of Cosmo Technologies Ltd,
`Ireland.
`
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