Alimentary Pharmacology and Therapeutics
`
`Clinical trial: evaluation of gastric acid suppression with three
`doses of immediate-release esomeprazole in the fixed-dose
`combination of PN 400 (naproxen⁄esomeprazole magnesium)
`compared with naproxen 500 mg and enteric-coated
`esomeprazole 20 mg: a randomized, open-label, Phase I study
`in healthy volunteers
`
`P. Miner Jr*, J. Plachetka , E. Orlemans , J. G. Fort  & M. Sostekà
`
`*Oklahoma Foundation for Digestive
`Research, Oklahoma City, OK, USA.
` POZEN Inc., Chapel Hill, NC, USA.
`àAstraZeneca US, Wilmington, DE,
`USA.
`
`Correspondence to:
`Dr P. Miner Jr, Oklahoma Foundation
`for Digestive Research, 1000 North
`Lincoln Boulevard, Suite 210,
`Oklahoma City, OK 73104, USA.
`E-mail: philip-miner@ouhsc.edu
`
`Publication data
`Submitted 1 April 2010
`First decision 13 April 2010
`Resubmitted 13 May 2010
`Accepted 16 May 2010
`Epub Accepted Article 18 May 2010
`
`414
`
`SUMMARY
`
`Background
`PN 400 is a fixed-dose combination formulated to provide sequential delivery
`of immediate-release (IR) esomeprazole and enteric-coated (EC) naproxen.
`
`Aim
`To evaluate gastric acid suppression with three doses of esomeprazole in
`PN 400 compared with EC esomeprazole 20 mg.
`
`Methods
`In this Phase I, randomized, open-label study, 28 healthy adults received
`PN 400 b.d. (naproxen 500 mg plus esomeprazole 10, 20 and 30 mg) and
`non-EC naproxen 500 mg b.d. plus EC esomeprazole 20 mg o.d., each for
`9 days in a crossover fashion. The primary endpoint was percentage of time
`on day 9 that intragastric pH was >4.0; secondary endpoints included phar-
`macokinetics and safety.
`
`Results
`Day 9 percentage of time where intragastric pH was >4.0 was 76.5%,
`71.4%, 40.9% and 59.9% for PN 400 containing 30, 20 and 10 mg esome-
`prazole, and naproxen plus esomeprazole 20 mg respectively. This was sig-
`nificantly greater for PN 400 containing 30 and 20 mg esomeprazole vs.
`naproxen plus esomeprazole 20 mg (95% CI: 13.0–26.0 and 7.8–20.7
`respectively). The pharmacokinetics of PN 400 were consistent with its for-
`mulation. No serious adverse events occurred.
`
`Conclusion
`PN 400 containing 20 mg esomeprazole was the lowest dose to achieve gas-
`tric acid suppression comparable to EC esomeprazole 20 mg and was
`selected for further evaluation.
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`
`ª 2010 Blackwell Publishing Ltd
`doi:10.1111/j.1365-2036.2010.04361.x
`
`Page 1
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`

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`
`INTRODUCTION
`are
`(NSAIDs)
`Nonsteroidal anti-inflammatory drugs
`among the most commonly used drugs worldwide, used
`by more than 30 million people every day.1 However,
`they are associated with a substantial risk of upper gas-
`trointestinal adverse events, ranging from ulcers to seri-
`ous ulcer complications such as perforation, obstruction
`and bleeding.2
`that
`recommend
`generally
`guidelines
`Treatment
`patients requiring chronic NSAID therapy who have risk
`factors
`for gastrointestinal ulcer
`complications
`(e.g.
`advanced age, a history of gastroduodenal ulcers or
`concomitant use of corticosteroids, aspirin and ⁄ or anti-
`coagulants3, 4) should be treated with cyclo-oxygenase-2
`selective NSAIDs or traditional, nonselective NSAIDs plus
`gastroprotective co-therapy. In particular, enteric-coated
`(EC) proton pump inhibitors have well-documented effi-
`cacy for reducing the incidence of NSAID-associated
`endoscopic ulcers and upper gastrointestinal
`symp-
`toms,5, 6 and are recognized as an effective gastroprotec-
`tive strategy for at-risk patients.4
`However, despite clinical guidelines, evidence from
`practice suggests that gastroprotective co-therapy strate-
`gies are underutilized by physicians7 and poorly adhered
`to by patients.8–11 Partly as a result of this, there has
`been growing interest in the use of fixed-dose combina-
`tion therapies of NSAIDs with gastroprotective agents in
`a single
`tablet
`to, among other potential benefits,
`improve patient adherence.
`PN 400 (VIMOVO; AstraZeneca, Wilmington, DE,
`USA and POZEN, Inc., Chapel Hill, NC, USA) is a
`fixed-dose combination of EC naproxen 500 mg and
`immediate-release (IR) esomeprazole 20 mg that is in
`development for the treatment of the signs and symp-
`toms of osteoarthritis, rheumatoid arthritis and ankylos-
`ing spondylitis in patients at risk for developing NSAID-
`associated gastric ulcers. Naproxen is a nonselective
`NSAID with a well-established efficacy and safety pro-
`file12–14 and esomeprazole is a proton pump inhibitor
`with effective gastric acid suppression15
`that, when
`administered as an EC preparation, has demonstrated
`clinical efficacy to reduce the occurrence of endoscopic
`gastric and duodenal ulcers in at-risk patients using
`NSAIDs.16 The PN 400 single-tablet formulation com-
`prising
`an EC naproxen core
`surrounded by
`an
`IR esomeprazole mantle has been designed to provide
`sequential delivery of
`gastroprotective
`esomeprazole
`before systemic exposure to naproxen.
`In this
`study,
`the pharmacokinetics, pharmacody-
`namics and safety of three different dose formulations of
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
`
`PN 400 were evaluated and compared with naproxen
`500 mg and EC esomeprazole 20 mg, with the aim of
`determining levels and time to exposure for these drugs,
`and determining the dose of IR esomeprazole in PN 400
`to provide gastric acid suppression similar to EC esomep-
`razole.
`
`MATERIALS AND METHODS
`
`Study design
`This was a prospective, randomized, Phase I, open-label,
`single-centre, cross-over study comprising four treatment
`periods that was conducted in the US between 3 April
`and 25 June 2007.
`On day 1 of the first treatment period, study partici-
`pants were randomized into one of
`four
`treatment
`sequences to receive each of four treatments for 9 days
`in a crossover fashion. There was a washout period of
`‡12 days between treatments (Table 1). Study medication
`was administered orally with 240 mL of water 60 min
`before standardized meals in the morning and evening.
`All study medication was administered at the study site
`by staff, with a mouth check performed to ensure treat-
`ment compliance.
`treatment
`into
`randomized
`were
`Participants
`sequences according to their unique treatment number,
`which was assigned consecutively from a randomization
`schedule provided by POZEN following completion of
`screening.
`The study was reviewed and approved by an Investi-
`gational Review Board at the study site and all partici-
`pants gave written, informed consent in accordance with
`the 1996 Declaration of Helsinki.
`
`Table 1 | Study treatment
`
`Treatment
`
`PN 400 ⁄ E30
`
`PN 400 ⁄ E20
`
`PN 400 ⁄ E10
`
`Study medication
`
`EC naproxen 500 mg ⁄ IR
`esomeprazole 30 mg b.d.
`EC naproxen 500 mg ⁄ IR
`esomeprazole 20 mg b.d.
`EC naproxen 500 mg ⁄ IR
`esomeprazole 10 mg b.d.
`
`Naproxen + EC E20
`
`Non-EC naproxen* 500 mg b.d.
`and EC esomeprazole 20 mg o.d.
`
`b.d., twice daily; EC, enteric coated; IR, immediate release; o.d.,
`once daily.
`
`*Non-EC naproxen was inadvertently used as a control instead
`of EC naproxen.
`
`415
`
`Page 2
`
`

`

`PP.. MMiinneerr JJrr eett aall..
`
`Participants
`Eligible participants were healthy adults aged 18–55 years
`who tested negative for Helicobacter pylori infection and
`had no history of peptic ulcer disease or other acid-
`related gastrointestinal symptoms. Participants with a
`history of hypersensitivity, allergy or intolerance to any
`NSAID or proton pump inhibitor were excluded from
`the study. Other exclusion criteria included the presence
`of any uncontrolled acute or chronic illness, any gastro-
`intestinal disorder causing impaired drug absorption and
`a history of alcohol or drug abuse.
`The ingestion of grapefruit juice was disallowed within
`10 days of first dose and throughout the study. The use
`of any concomitant medications was not permitted
`unless approved by the principal investigator. Specifically,
`the use of any proton pump inhibitor or gastroprotective
`agent, any misoprostol-containing product,
`sucralfate,
`antibiotics, antacid or Pepto-Bismol (Procter & Gamble,
`Cincinnati, OH, USA) was disallowed within 14 days
`prior to dosing and throughout the study. Additionally,
`within 7 days prior to dosing and throughout the study,
`the use of any NSAID, bisphosphonate, steroid, anticoag-
`ulant, anticholinergic or monoamine oxidase inhibitor
`was also disallowed.
`During a screening period of up to 14 days, partici-
`pants were assessed for eligibility; a physical exam and
`12-lead electrocardiogram were performed; vital signs
`were recorded and clinical
`laboratory samples were
`taken. Participants returned on day 0, when eligibility
`and vital signs were reviewed again and those who con-
`tinued to meet eligibility criteria remained at the study
`site to enter the treatment phase.
`
`Study endpoints
`The primary pharmacodynamic endpoint was the per-
`centage of time over 24 h on day 9 of each treatment
`phase that intragastric pH was >4.0. The percentage of
`time over 24 h on day 1 that intragastric pH was >4.0
`was assessed as a secondary endpoint. The percentage of
`time that intragastric pH was >3.0 and >5.0 on days 1
`and 9 was also assessed.
`Intragastric pH was measured by a pH probe (Digitrap-
`per pH data logger; Medtronics, Minneapolis, MN, USA)
`placed prior to administration of study medication on day
`1, with the distal electrode 10 cm below the lower oesoph-
`ageal sphincter and the proximal electrode 5 cm above.
`The pH probe was removed in the morning of day 2 prior
`to morning (AM) dosing. This was repeated on day 9, with
`the probe removed on day 10. Collected pH data were
`evaluated by a third party blinded to study treatment.
`
`416
`
`On days 1 and 9 of each treatment period, pre-AM
`dose and serial post-AM dose blood samples were col-
`lected for pharmacokinetic (PK) assessments. Final blood
`samples were collected predose in the morning of day 2
`and following completion of treatment on day 10.
`The following PK parameters for esomeprazole and
`naproxen were calculated for each treatment after the AM
`and afternoon (PM) doses: peak plasma concentration
`(Cmax,AM and Cmax,PM), time to peak plasma concentration
`(tmax,AM and (tmax,PM), area under the plasma concentra-
`tion vs. time curve from time zero to the last time point
`with measurable drug concentration (AUC0–t,AM and
`AUC0–t,PM) and half-life (t½). AUC from time zero (time
`of dosing) to 10 h post-AM dose (AUC0–10,AM), AUC from
`time zero to 14 h post-PM dose (AUC0–14,PM) and a total
`daily AUC (AUC0–24) were also calculated.
`Safety for each treatment was assessed by the inci-
`dence of adverse events, a physical examination, vital
`signs and the following clinical
`laboratory tests: creati-
`nine, alanine aminotransferase, aspartate aminotransfer-
`ase, haematocrit, alkaline phosphatase, bilirubin, blood
`urea nitrogen, complete blood count and complete uri-
`nalysis.
`Adverse events were recorded from the start of treat-
`ment until the final visit and were assessed for severity
`and relationship to study drug. Clinical laboratory tests,
`physical examination and measurement of vital signs
`were performed at screening and the final visit (on com-
`pletion of the fourth treatment period or discontinua-
`tion). Vital signs were also measured in the PM of all
`days 0 and 8 visits, and complete blood count (without
`differential) was repeated on day 8 of the first three
`treatment periods and day 0 of the fourth period.
`
`Statistical analysis
`This study planned to enrol 28 subjects with the goal of
`having 24 evaluable subjects for analysis. A total of
`24 subjects provided 80% power to reject the null hypoth-
`esis that the difference between each of the PN 400 treat-
`ments and the active control treatment in percentage of
`time that pH was >4.0 over 24 h was £)8% using a pair-
`wise t-test with a one-sided significance level of 0.05.
`All statistical analyses were completed using the SAS
`system, version 8.2 or higher (SAS Institute Inc., Cary,
`NC, USA). The intent-to-treat (ITT) population was
`defined as all randomized participants who had valid pH
`data for at least one treatment period (received all doses
`of study medication during that treatment period, had at
`least 20 h of valid pH data determined by the clinical
`investigator, did not have technical failures of the pH
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
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`
`recording and did not have ‡1 continuous hour with pH
`data outside the reference range). Primary pharmacody-
`namic analyses were based on the per protocol popula-
`tion (participants in the ITT population who had valid
`pH data for all four treatment periods and did not vio-
`late the protocol
`in any major way that would have
`impacted the evaluation of pharmacodynamic endpoints).
`The percentage of time that pH was >4.0 on days 1 and
`9 was summarized by treatment and analysed by analysis
`of variance. The least squares (LS) means for each treat-
`ment, the difference of LS means between each of the
`PN 400 treatments and the active control and 95% confi-
`dence intervals (CIs) for all treatment differences were
`calculated.
`Pharmacokinetic analyses were performed on the PK
`population (all randomized participants who received all
`doses of study medication for at least one treatment per-
`iod and had adequate blood sampling to determine the
`PK parameters of the study drugs).
`Plasma esomeprazole and naproxen concentration
`data were summarized by treatment and study day at
`each sampling time using descriptive statistics including
`mean, standard deviation, % coefficient of variance, med-
`ian, minimum and maximum. Geometric mean and
`associated 95% CIs were also calculated for all PK
`parameters, except tmax. Plasma concentrations below the
`lower limit of quantification were treated as a zero value
`for calculating descriptive statistics. The mean ⁄ median
`value at a time point with ‡1 value below the lower limit
`of quantification was reported unless the mean ⁄ median
`value was below the lower limit of quantification of the
`assay, in which case, the value was reported as below the
`lower limit of quantification.
`The plasma concentration vs. time data of each ana-
`lyte were subjected to noncompartmental analysis using
`WinNonlin version 4.1 (Pharsight Corporation, Moun-
`tain View, CA, USA). Statistical analysis was performed
`using analysis of variance to determine the point esti-
`mate and associated 90% CI of the days 9 to 1 ratios for
`the following parameters: Cmax,AM, Cmax,PM, AUC0–10,AM,
`AUC0–14,PM and AUC0–24. Natural log-transformed Cmax
`and AUC values were used for the analyses, thus geomet-
`ric LS mean ratios for each parameter were determined.
`Safety analyses were based on the safety population
`(all subjects who received at least one dose of study med-
`ication). Adverse events were coded by system organ
`class and preferred term according to the Medical Dictio-
`nary for Regulatory Activities (MedDRA, version 8.0).
`Vital signs and clinical laboratory test results were sum-
`marized by visit.
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
`
`RESULTS
`
`Participants
`Twenty-eight participants were randomized to treatment
`and 27 completed the study (Figure 1). A majority of
`participants were male (68%) and all were white. Mean
`age was 24.9 years. Demographics and baseline charac-
`teristics of enrolled participants are shown in Table 2.
`
`Pharmacodynamics
`On day 9, the mean percentage of time where intragastric
`pH was >4.0 over 24 h was 76.5%, 71.4%, 40.9% and
`59.9% for PN 400 ⁄ E30, PN 400 ⁄ E20, PN 400 ⁄ E10 and
`naproxen + EC E20 respectively (Table 3). Compared
`with naproxen + EC E20 treatment, this percentage was
`significantly greater for PN 400 ⁄ E30 and PN 400 ⁄ E20
`(95% CI: 13.0–26.0 and 7.8–20.7 respectively), but was
`significantly less for treatment with PN 400 ⁄ E10 (95% CI:
`)22.3 to 9.7). Treatment with PN 400 ⁄ E10 also resulted
`in the greatest variability of all treatments, as indicated by
`the high co-efficient of variation (Table 3).
`Compared with observations on day 9, the mean per-
`centage of time with intragastric pH >4.0 over 24 h was
`lower on day 1 for all treatment groups (27.8%, 20.5%,
`12.8% and 21.3% for PN 400 ⁄ E30, PN 400 ⁄ E20,
`
`Figure 1 | Subject disposition. aPremature withdrawal for
`personal reasons; bOn day 9 of period 4 (PN 400 ⁄ E20)
`prior to completion of pH monitoring; cOn day 9 of
`period 3 (naproxen + EC E20). ITT, intent-to-treat; PK,
`pharmacokinetic; PP, per protocol.
`
`417
`
`Page 4
`
`

`

`–
`
`–
`
`21.5(3.3)
`
`3.2–58.2
`
`64
`
`16.8
`
`)(15.3–2.4)
`
`)(7.3–5.4)
`
`0.0–12.8
`
`)8.9(3.2)
`12.7(3.4)
`
`3.0–53.8
`
`)0.92(3.2)
`20.6(3.3)
`
`4.4–74.4
`
`87
`
`9.1
`
`81
`
`15.3
`
`6.4(3.2)
`
`27.9(3.3)
`
`1.8–89.6
`
`81
`
`20.0
`
`21.3(13.6)
`
`12.8(11.1)
`
`20.5(16.6)
`
`27.8(22.6)
`
`n=25
`Naproxen+ECE20,
`
`n=24
`PN400⁄E10,
`
`n=25
`PN400⁄E20,
`
`n=25
`PN400⁄E30,
`
`PP.. MMiinneerr JJrr eett aall..
`
`Table 2 | Baseline demographics (ITT population)
`
`Age (years)
`
`Mean (s.d.)
`
`Median
`
`Range
`
`Gender, n (%)
`
`Male
`
`Female
`
`Race, n (%)
`
`White
`
`Height (inches)
`
`Mean (s.d.)
`
`Median
`
`Range
`
`Total participants
`(n = 28)
`
`24.9 (3.9)
`
`24
`
`18–34
`
`19 (68)
`
`9 (32)
`
`28 (100)
`
`70.1 (4.1)
`
`70.0
`
`63–79
`
`PP,perprotocol;EC,entericcoated;s.d.,standarddeviation;LS,least-squares;S.E.,standarderror;CI,confidenceinterval.
`
`)(22.3–9.7)
`
`7.8–20.7
`
`13.0–26.0
`
`95%CI
`
`–
`
`–
`
`57.2(3.0)
`
`40.6–75.5
`
`18
`
`55.1
`
`)16.1(3.3)
`41.1(3.0)
`
`10.3–85.3
`
`55
`
`35.8
`
`14.2(3.3)
`
`71.5(3.0)
`
`51.8–97.6
`
`18
`
`70.4
`
`19.5(3.3)
`
`76.8(3.0)
`
`49.8–95.3
`
`16
`
`78.8
`
`56.9(10.1)
`
`40.9(22.5)
`
`71.4(13.0)
`
`76.5(12.3)
`
`n=25
`Naproxen+ECE20,
`
`n=25
`PN400⁄E10,
`
`n=25
`PN400⁄E20,
`
`n=25
`PN400⁄E30,
`
`Day1
`
`Day9
`
`Table3|PercentageoftimewithgastricpH>4.0over24hondays9and1(PPpopulation)
`
`Weight (lb)
`
`Mean (s.d.)
`
`Median
`
`Range
`
`177.9 (34.6)
`
`178.0
`
`112–250
`
`ITT, intent-to-treat; s.d., standard deviation.
`
`PN 400 ⁄ E10 and naproxen + EC E20 respectively)
`(Table 3), although a similar pattern was observed with
`PN 400 ⁄ E30 treatment, resulting in a greater percentage
`of time with intragastric pH >4.0 over 24 h compared
`with naproxen + EC E20 treatment (95% CI: 0.0–12.7).
`As expected, compared with values reported for the
`percentage of time with intragastric pH >4.0 over 24 h,
`these percentages were higher for pH >3.0 and lower for
`pH >5.0 for all treatment groups on days 1 and 9 (data
`not shown). However, a similar treatment pattern was
`observed, with greater percentages
`reported for
`the
`PN 400 ⁄ E30 and PN 400 ⁄ E20 treatment groups com-
`pared with the naproxen + EC E20 treatment group.
`On day 1, mean intragastric pH was low, ranging
`between pH 1.0 and 2.0, following an overnight fast and
`prior to any treatment (Figure 2b). By day 9, the range
`following overnight fast had increased to pH 2.0–3.0 for
`all treatments (Figure 2a).
`Three pH surges were observed over 24 h on days 1
`and 9, occurring approximately 1 h after food intake for
`all treatments at 1, 6 and 11 h (Figure 2). On day 9,
`esomeprazole in all treatments was observed to have a
`dose-related effect on gastric pH beyond the influence of
`
`418
`
`ECE20(S.E.)
`LSmeandifferencevs.naproxen+
`
`LSmean(S.E.)
`
`Range
`
`%coefficientofvariation
`
`Median
`
`Mean(s.d.)
`
`TimepH>4.0(%)
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
`
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`doses on days 1 and 9 are summarized in Table 4. The
`steady-state EC naproxen plasma profiles were compara-
`ble among the three PN 400 treatments.
`Following AM or PM doses on days 1 and 9, plasma IR
`esomeprazole concentrations
`increased with the eso-
`meprazole dose across the three PN 400 treatments. On
`both days, the measurable plasma concentrations of IR
`esomeprazole were higher following the AM dose than
`the PM dose for all three PN 400 treatments (Figure 3a–
`b).
`
`On day 1, quantifiable plasma concentrations of IR
`esomeprazole were obtained rapidly with all
`three
`PN 400 treatments at 10 min after the AM dose, and at
`20–30 min after administration of
`the PM dose (Fig-
`ure 3a). IR esomeprazole was rapidly eliminated from
`plasma in the majority of subjects by 6–8 h postdose (AM
`and PM) for all three PN 400 treatments (Figure 3a).
`On day 9, pre-AM dose blood samples showed that
`esomeprazole concentrations were quantifiable in 19 sub-
`receiving PN 400 ⁄ E30 treatment, 13 receiving
`jects
`PN 400 ⁄ E20 treatment and six receiving PN 400 ⁄ E10
`treatment. Post-AM and PM dose samples showed that in
`the PN 400 treatments containing higher IR esomepraz-
`ole doses (PN 400 ⁄ E30 and PN 400 ⁄ E20), plasma con-
`centrations of esomeprazole were quantifiable at earlier
`postdose time points in a large number of subjects and
`for a longer period compared with day 1 (Figure 3b).
`Following administration of naproxen + EC E20 treat-
`ment on days 1 and 9, measurable plasma concentrations
`of EC esomeprazole were not available until 0.75–1.5 h
`postdose in the majority of subjects and were measurable
`for longer than concentrations following PN 400 admin-
`istration (Figure 3a,b).
`The mean plasma profiles of EC naproxen were
`comparable following the three PN 400 treatments,
`particularly on day 9 (Figure 3c,d), demonstrating
`delayed-release characteristics consistent with the EC for-
`mulation in PN 400, with higher mean plasma naproxen
`concentration levels observed at the end of a 24-h interval.
`On day 1, quantifiable plasma concentrations of EC
`naproxen were first detected at approximately 2 h post-
`PN 400 administration for all three PN 400 treatments
`(Figure 3c). By day 9, pre-AM dose samples showed that
`EC naproxen concentrations were quantifiable in all par-
`ticipants
`throughout
`the entire sampling time (Fig-
`ure 3d), and mean plasma concentrations were much
`higher than observed on day 1.
`Following non-EC naproxen treatment on days 1 and
`9, plasma naproxen concentrations were measurable in
`all subjects at the 10-min postdose sample time and for
`
`419
`
`Figure 2 | (a) Mean intragastric pH over 24 h on day
`9; (b) mean intragastric pH over 24 h on day 1 (PP
`population). PP, per protocol; EC, enteric coated.
`
`food intake. Following administration of the morning
`dose of PN 400 formulations,
`rapid, dose-related
`increases in pH were observed approximately 1 h earlier
`than food-induced increases in pH (Figure 2a). In con-
`trast,
`there was a comparative delay in pH increase
`related to morning administration of EC E20 with nap-
`roxen + EC E20 treatment.
`After 9 days of treatment, PN 400 ⁄ E30 and PN 400 ⁄
`E20 had a similar effect on gastric pH with an observed
`slower return to low pH levels after food intake com-
`pared with PN 400 ⁄ E10 and naproxen + EC E20. In
`contrast, on day 1, doses of esomeprazole in any treat-
`ment had a minimal effect on gastric pH beyond the
`effect of food intake (Figure 2b).
`
`Pharmacokinetics
`The PK parameters of esomeprazole and naproxen for
`all treatments following administration of the AM and PM
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
`
`Page 6
`
`

`

`PP.. MMiinneerr JJrr eett aall..
`
`Table 4 | Summary of esomeprazole and naproxen pharmacokinetic parameters on days 1 and 9 (PK population)
`
`tmax (h)
`
`AUC*
`(hÆng ⁄ mL)
`
`Naproxen
`
`Cmax
`(ng ⁄ mL)
`
`tmax (h)
`
`0.50 (0.33–1.50)
`
`591 (108)
`
`48.1 (53)
`
`4.00 (2.00–10.00)
`
`1.50 (0.33–4.00)
`
`388 (137)
`
`68.9 (28)
`
`14.00 (0.50–14.00)
`
`AUC*
`(hÆng ⁄ mL)
`
`259 (56)
`
`471 (30)
`
`0.50 (0.20–1.50)
`
`1.49 (0.33–3.00)
`
`350 (113)
`
`206 (141)
`
`44.4 (68)
`
`4.00 (2.00–10.00)
`
`231 (70)
`
`71.5 (26)
`
`14.00 (0.00–14.00)
`
`450 (33)
`
`Esomeprazole
`
`Treatment, day
`and dose
`
`Cmax
`(ng ⁄ mL)
`
`PN 400 ⁄ E30 (n = 28)
`Day 1, AM
`487 (82)
`
`Day 1, PM
`187 (132)
`PN 400 ⁄ E20 (n = 28)
`Day 1, AM
`292 (77)
`
`Day 1, PM
`96.6 (104)
`PN 400 ⁄ E10 (n = 27)
`Day 1, AM
`
`138 (71)
`
`0.33 (0.17–3.10)
`
`148 (111)
`
`57.0 (31)
`
`4.00 (2.00–10.00)
`
`Day 1, PM
`
`35.3 (84)
`
`1.50 (0.33–3.00)
`
`85.7  (179)
`
`68.6 (26)
`
`10.00 (0.00–14.00)
`
`Naproxen + EC E20 (n = 28)
`
`Day 1, AM
`
`282 (66)
`
`1.50 (1.00–16.00)
`
`540  (60)
`
`65.5 (25)
`
`1.50 (0.75–6.00)
`
`1.50 (0.50–2.50)
`
`310 (35)
`
`508 (29)
`
`409 (16)
`
`685 (10)
`
`81.5 (14)
`
`0.50 (0.17–1.50)
`
`1.00 (0.33–8.00)
`
`2779 (45)
`
`2066 (53)
`
`80.9 (23)
`
`76.2 (23)
`
`3.00 (0.00–8.00)
`
`603 (21)
`
`10.40 (0.00–14.00)
`
`648 (20)
`
`0.50 (0.17–1.50)
`
`0.75 (0.33–3.00)
`
`1216 (69)
`
`919 (84)
`
`86.2 (22)
`
`76.8 (18)
`
`3.00 (0.00–8.05)
`
`10.00 (0.00–14.00)
`
`607 (19)
`
`678 (16)
`
`0.33 (0.17–1.00)
`
`368 (89)
`
`223  (134)
`
`87.1 (21)
`
`78.6 (17)
`
`2.50 (0.00–8.00)
`
`14.00 (1.50–14.00)
`
`637 (17)
`
`672 (19)
`
`Day 1, PM
`PN 400 ⁄ E30 (n = 28)
`Day 9, AM
`1584 (39)
`
`Day 9, PM
`810 (59)
`PN 400 ⁄ E20 (n = 27)
`Day 9, AM
`715 (52)
`
`Day 9, PM
`428 (73)
`PN 400 ⁄ E10 (n = 27)
`Day 9, AM
`278 (57)
`
`Day 9, PM
`
`97.6 (136)
`
`1.00 (0.33–2.00)
`
`Naproxen + EC E20 (n = 28)
`
`Day 9, AM
`
`Day 9, PM
`
`435 (48)
`
`1.50 (1.00–14.00)
`
`1046 (54)
`
`–
`
`–
`
`–
`
`90.0 (19)
`
`86.5 (13)
`
`1.50 (0.50–4.00)
`
`1.50 (0.75–4.00)
`
`617 (12)
`
`769 (10)
`
`Values are mean (% coefficient of variation) for Cmax and AUC, and median (range) for tmax.
`PK, pharmacokinetic; Cmax, peak plasma concentration; tmax, time to peak plasma concentration; AUC, area under the plasma con-
`centration vs. time curve.
`*AUC0–10,AM or AUC0–14,PM.
` n = 26.
`
`up to 24 h, consistent with a non-EC naproxen formula-
`tion (Figure 3c,d).
`
`Safety
`tolerated. The
`In general, study treatments were well
`overall
`incidence of adverse events ranged from 29%
`with naproxen + EC E20 to 50% with PN 400 ⁄ E30 and
`PN 400 ⁄ E20. A majority were mild and no participants
`reported serious adverse events or withdrew from the
`study due to adverse events.
`
`The most common adverse events (reported by ‡10%
`of participants during any treatment) were diarrhoea,
`upper abdominal pain,
`iron deficiency and headache
`(Table 5). Gastrointestinal adverse events were reported
`in 29–32% of subjects receiving PN 400 treatments and
`18% of subjects receiving naproxen + EC E20 (Table 5).
`The incidence of treatment-related adverse events was
`39% (n = 11), 29% (n = 8), 26% (n = 7) and 21%
`(n = 6) during treatment with PN 400 ⁄ E30, PN 400 ⁄ E20,
`PN 400 ⁄ E10 and naproxen + EC E20 respectively. The
`
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`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
`
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`most frequent treatment-related adverse events reported
`by ‡10% of participants during any treatment were gastro-
`intestinal and nervous system disorders, including diar-
`rhoea (n = 2–4), upper abdominal pain (n = 0–3) and
`headache (n = 0–3).
`Decreases in haematocrit, haemoglobin and ⁄ or red
`blood cell counts throughout the study were observed in
`all 28 participants. However, most cases were small devi-
`ations from the normal range and were not considered
`by the investigator to be related to study treatment, but
`as a result of blood sampling throughout the study. Vital
`sign measurements and physical examinations were simi-
`lar at screening and the final visit.
`
`DISCUSSION
`IR esomeprazole 20 mg or
`This
`study showed that
`30 mg in PN 400 b.d. provided gastric acid suppression
`comparable to EC esomeprazole 20 mg o.d. The study
`also demonstrated that PN 400 provided early onset of
`increased intragastric pH at steady state before EC nap-
`roxen was released. In addition, following administration
`of the PN 400 formulations, IR esomeprazole was rapidly
`absorbed with relatively high plasma concentrations mea-
`surable at an earlier
`time postdose compared with
`EC esomeprazole. Thus, the PK parameters and plasma
`profiles of esomeprazole and naproxen, together with the
`intragastric pH profiles obtained on day 9, were consis-
`tent with the sequential-release design of PN 400 to
`achieve rapidly a gastroprotective environment.
`It is understood that NSAID-associated gastroduode-
`nal damage can be substantially reduced by elevating the
`luminal pH above 4.0.17 Our results are comparable to
`previous studies that reported that, after 5 days of o.d.
`dosing, the percentage of time that gastric pH was >4.0
`was approximately 50% for EC E20 and 70% for EC
`E40.15, 18 Both of these dosages have also been approved
`for
`the
`risk reduction of NSAID-associated gastric
`ulcer.16 In this study, PN 400 containing 20 or 30 mg of
`IR esomeprazole resulted in greater time with pH >4.0
`over 24 h on day 9 than the control treatment of nap-
`roxen 500 mg b.d. and EC esomeprazole 20 mg o.d.
`given separately.
`Based on these results, where PN 400 ⁄ E10 provided
`highly variable and insufficient pH control, and PN 400 ⁄
`E30 was not significantly better than PN 400 ⁄ E20 in pro-
`viding additional pH control, PN 400 ⁄ E20 was selected
`for further studies to evaluate the gastrointestinal and
`analgesic efficacy of PN 400. Indeed, in a recent Phase 3
`study, PN400 ⁄ E20 demonstrated a significant reduction
`
`Figure 3 | (a) Mean plasma esomeprazole concentration
`vs. time on day 1; (b) mean plasma esomeprazole con-
`centration vs. time on day 9; (c) mean plasma naproxen
`concentration vs. time on day 1; (d) mean plasma nap-
`roxen concentration vs. time on day 9 (PK population).
`PK, pharmacokinetic; EC, enteric coated.
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
`
`421
`
`Page 8
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`PP.. MMiinneerr JJrr eett aall..
`
`Table 5 | Clinical adverse events (Safety population), n (%)
`
`Participants with ‡1 adverse event
`Gastrointestinal disorders
`
`Diarrhoea
`
`Abdominal distension
`
`Dyspepsia
`
`Abdominal pain (upper)
`
`Constipation
`
`Epigastric discomfort
`
`Gastroenteritis (viral)
`
`Abdominal pain (lower)
`
`Metabolism and nutrition disorders
`
`Iron deficiency
`
`General disorders
`
`Fatigue
`
`Influenza-like illness
`
`Nervous system disorders
`
`Headache
`
`Dizziness
`
`EC, enteric coated.
`
`PN 400 ⁄ E30
`(n = 28)
`
`14 (50.0)
`
`9 (32.1)
`
`4 (14.3)
`
`2 (7.1)
`
`1 (3.6)
`
`3 (10.7)
`
`1 (3.6)
`
`1 (3.6)
`
`0 (0.0)
`
`0 (0.0)
`
`3 (10.7)
`
`3 (10.7)
`
`1 (3.6)
`
`1 (3.6)
`
`0 (0.0)
`
`4 (14.3)
`
`3 (10.7)
`
`1 (3.6)
`
`PN 400 ⁄ E20
`(n = 28)
`
`14 (50.0)
`
`8 (28.6)
`
`4 (14.3)
`
`2 (7.1)
`
`2 (7.1)
`
`0 (0.0)
`
`1 (3.6)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (3.6)
`
`5 (17.9)
`
`5 (17.9)
`
`2 (7.1)
`
`1 (3.6)
`
`1 (3.6)
`
`1 (3.6)
`
`1 (3.6)
`
`0 (0.0)
`
`PN 400 ⁄ E10
`(n = 27)
`
`9 (33.3)
`
`8 (29.6)
`
`3 (11.1)
`
`2 (7.4)
`
`1 (3.7)
`
`1 (4.0)
`
`1 (3.7)
`
`1 (3.7)
`
`2 (7.4)
`
`0 (0.0)
`
`1 (3.7)
`
`1 (3.7)
`
`1 (3.7)
`
`1 (3.7)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`Naproxen
`+ EC E20
`(n = 28)
`
`8 (28.6)
`
`5 (17.9)
`
`2 (7.1)
`
`2 (7.1)
`
`1 (3.6)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (3.6)
`
`1 (3.6)
`
`1 (3.6)
`
`1 (3.6)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`endoscopic gastric ulcers and
`incidence of
`in the
`improved upper gastrointestinal
`tolerability compared
`with EC naproxen 500 mg alone in at-risk patients with
`arthritis.19, 20
`A site error resulted in the use of a non-EC formula-
`tion of naproxen in the control treatment. This error
`was identified after study completion following the dis-
`covery of atypical PK results. However, as the plasma
`concentrations of IR esomeprazole were measurable ear-
`lier than non-EC naproxen on day 9, this error does not
`affect the study interpretation.
`Perhaps surprisingly, the absorption of IR esomepra-
`zole following the PM dose of PN 400 was delayed com-
`pared with AM dosing,
`and plasma
`esomeprazole
`concentrations after the PM dose were lower than after
`the AM dose. This may be explained by slower gastric
`emptying time following lunch and dinner on the day of
`dosing. Increased gastric residence time may also have
`resulted in some degradation of esomeprazole from
`PN 400 and the prolonged tmax observed after the PM
`dose on days 1 and 9. The
`increase
`in plasma
`
`esomeprazole concentrations with repeated doses of PN
`400 may be attributed to reduced degradation along with
`decreased systemic drug metabolism via inhibition of
`cytochrome P450 2C19 by esomeprazole.21
`This study was also able to demonstrate a lack of PK
`drug–drug interactions between EC naproxen and IR
`esomeprazole when co-administered as a fixed-dose com-
`bination. This can be interpreted from the finding that
`the dose level of IR esomeprazole in PN 400 did not
`affect the steady-state plasma exposure to naproxen.
`In the present study, PN 400 containing 30, 20 or
`10 mg of IR esomeprazole was well tolerated in 9-day
`b.d. treatment periods in healthy subjects. The incidence
`of all adverse events experienced with PN 400 was some-
`what higher than with naproxen + EC E20, including the
`incidence of gastrointestinal events (diarrhoea, upper
`abdominal pain). The apparent increase in treatment-
`related adverse events observed with increasing dose of
`IR esomeprazole in the three different PN 400 formula-
`tions suggests that some of these adverse events may be
`related to esomeprazole rather than to EC naproxen.
`
`422
`
`Aliment Pharmacol Ther 2010; 32: 414–424
`ª 2010 Blackwell Publishing Ltd
`
`Page 9
`
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`However, these findings must be int