ORIGINAL RESEARCH ARTICLE
`
`Clln Drug Invest 2005; 25 (11): 731-740
`1173-2563/05/0011-0731/$34.95/0
`© 2005 Adis Data Information BV.All rights reserved.
`
`Lack of Pharmacokinetic Interaction
`between Esomeprazole and the
`Nonsteroidal Anti-Inflammatory
`Drugs Naproxen and Rofecoxib in
`Healthy Subjects
`M.Hassan-Alin,']. Naesdal,' C. Nilsson-Pieschl,| G. Langstrém! and T. Andersson?
`
`1 AstraZeneca R&D Mélndal, Mélndal, Sweden
`2 AstraZeneca LP, Wilmington, Delaware, USA
`
`Abstract
`
`Background: Weinvestigated the potential interactions between esomeprazole
`and a non-selective nonsteroidal anti-inflammatory drug (NSAID; naproxen) or a
`cyclo-oxygenase (COX)-2-selective NSAID (rofecoxib) in healthy subjects.
`Methods: Twostudies of identical randomised, open, three-way crossover design
`were conducted. Subjects (n = 32 for both studies) were to receive 1 week’s
`treatment with esomeprazole 40mg oncedaily (studies A and B), naproxen 250mg
`twice daily (study A), rofecoxib 12.5mg once daily (study B), and esomeprazole
`in combination with naproxen (study A) or rofecoxib (study B). Study periods
`were separated by a 2-week washoutperiod.
`
`Results: On day 7 of dosing, the ratios (and 95% CIs) for the area under the
`plasma concentration-time curve during the dosing interval (AUC;) and observed
`maximum plasma concentration (Cmax) of esomeprazole and NSAID combina-
`tion/NSAID alone were 0.98 (0.94, 1.01) and 1.00 (0.97, 1.04), respectively, for
`study A, and 1.15 (1.06, 1.24) and 1.14 (1.02, 1.28), respectively, for study B. The
`ratios (and 95% CIs) for AUC; and Cmax of esomeprazole and NSAID combina-
`tion/esomeprazole alone were 0.96 (0.89, 1.03) and 0.92 (0.85, 1.00), respective-
`ly, for study A, and 1.05 (0.96, 1.15) and 1.05 (0.94, 1.18), respectively, for study
`B. All treatments were well tolerated during the study period.
`Conclusion: Naproxen and rofecoxib do not interact with esomeprazole, and
`esomeprazole does not affect the pharmacokinetics of naproxen or rofecoxib.
`These findings indicate that esomeprazole can be used in combination with
`NSAIDswithout the risk of a pharmacokinetic interaction.
`
`DRL EXHIBIT 1016 PAGE 1
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`

`

`732
`
`Hassan-Alin etal.
`
`Nonsteroidal anti-inflammatory drugs (NSAIDs)
`are widely used for the treatment of rheumatoid
`arthritis (RA), osteoarthritis (OA) and a wide variety
`of other acute and chronic painful musculoskeletal
`disorders, and can, in most countries, be used as
`standard analgesics and bought without a prescrip-
`tion. There were over 111 million NSAID prescrip-
`tions in the US for the year ending August 2000,
`with one-third of the total number of prescriptions
`being
`for
`cyclo-oxygenase
`(COX)-2-selective
`NSAIDs."! The use of NSAIDsis expected to in-
`crease further in the future, especially if they be-
`come more widely used for the prevention of
`colorectal cancer and Alzheimer’s disease. The use
`
`of low-dose aspirin for cardiovascular protection is
`also expected to increase.
`
`All NSAIDsare, however, associated with a sub-
`stantial number of adverse events, with non-selec-
`tive NSAIDs accounting for 20% and 25% ofall
`reported adverse drug events in the UK and US,
`respectively.23]1 NSAID-associated upper gastro-
`intestinal (GD) tract adverse effects range from dys-
`peptic symptomsto peptic ulceration and ulcer com-
`plications.“ Some 15-40% of NSAIDusers report
`upper GI symptoms! and 10-30% of long-term
`NSAID users will develop a peptic ulcer, predomi-
`nantly in the stomach.'©71 NSAID useincreases the
`risk of peptic ulcer complications by 3- to 5-fold,
`and 15-35% of all peptic ulcer complications are
`reported to be caused by NSAID use."4!
`It has been estimated that
`there are over
`
`and
`year
`per
`admissions
`hospital
`100000
`16 500 deaths per year due to NSAID-induced GI
`complications in the US.®!
`
`The anti-inflammatory properties of NSAIDsare
`mediated through the inhibition of the COX-2 en-
`zyme, whereas GI adverse effects occur as a result
`of
`their
`action
`on COX-1. COX-2-selective
`
`NSAIDs,such as celecoxib and rofecoxib, preferen-
`tially inhibit COX-2. One conclusion of the VIGOR
`(Vioxx GI Outcomes Research) study, which com-
`
`pared naproxen with rofecoxib in patients with RA,
`wasthat treatment with rofecoxib was associated
`
`with significantly fewer upper GI events than treat-
`ment with naproxen.! Celecoxib was compared
`with ibuprofen and diclofenac in a similar study.
`The annual rates of upper GI complications were
`lower for celecoxib compared with ibuprofen and
`diclofenac, but the difference did not reach statisti-
`cal significance, and the combination of celecoxib
`and low-dose (<325 mg/day) aspirin negated the GI
`advantage of celecoxib."It is also worth noting
`that in this trial, the doses of celecoxib used were
`2—4 times the maximum recommendeddosesfor the
`
`treatment of RA and OA.
`
`Unfavourable cardiovascular risk data has led
`
`re-evaluation of the use of the
`to an urgent
`COX-2-selective class of NSAIDsin clinical prac-
`tice, culminating in the market suspension of the
`COX-2-selective agents rofecoxib and valdecox-
`ib.“12] The US FDAhasrequested that manufactur-
`ers of all marketed prescription NSAIDs revise
`product labeling to include a boxed warning high-
`lighting the potential for increased risk of cardiovas-
`cular events, and is encouraging physicians to limit
`the use of COX-2-selective agents to the lowest
`practical dose for the most urgent cases.!3] All
`COX-2-selective agents available in Europe contain
`cardiovascular warnings, and prescribers are ad-
`vised to carefully regard the warnings in patients
`with a history of cardiovascular disease."Celecox-
`ib is still available in the US, and celecoxib and
`various other COX-2-selective agentsare still avail-
`able in Europe.!3141 Additionally, during the first
`quarter of 2005, an FDA advisory panel recom-
`mendedthat rofecoxib should again be madeavaila-
`ble to patients, and that black-box warnings be
`placed on the labels of all COX-2-selective
`agents.">161 Canadian health authorities may also be
`moving towards approving the return of rofecoxib to
`the market."7] Consequently, it does seem likely
`that,
`in the future, a range of COX-2-selective
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
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`

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`No Pharmacokinetic Interaction between Esomeprazole and Naproxen/Rofecoxib
`
`733
`
`agents maystill have a role to play in the effective
`managementof certain patients with low cardiovas-
`cular risk.
`
`The proton pumpinhibitor (PPI) omeprazole has
`been shown to be superior to ranitidine and miso-
`prostol for both the healing and the prevention of
`NSAID-associated ulcers and dyspeptic symptoms
`during continued NSAIDtreatment."'®"9! The degree
`of gastric damage caused by NSAIDsis highly
`dependent on intragastric pH."'82°] Esomeprazole,
`which confers a longer time with intragastric pH >4
`than all other PPIs,?"! is expected to be effective for
`the prevention of NSAID-associated ulcers.
`Asesomeprazole is expected to be widely used in
`the healing and prevention of gastric and duodenal
`ulcers, and to control upper GI symptomsin patients
`needing continuous NSAID treatmentto relieve in-
`flammation and pain,it is important to rule out any
`drug-drug interactions between esomeprazole and
`NSAIDs,
`including non-selective and selective
`agents. In order to test for pharmacokinetic inter-
`actions between esomeprazole and naproxen,a pop-
`ular non-selective NSAID,
`and between eso-
`meprazole and rofecoxib, a previously popular
`COX-2-selective NSAID that maystill be a benefi-
`cial drug in carefully selected patients, we conduct-
`ed two identically designed studies in healthy sub-
`jects.
`
`Materials and Methods
`
`Subjects
`
`Healthy subjects were included if they: were
`20-50 years old; had a body mass index of
`19-27 kg/m2; weighed 50-95kg; showed normal
`physical findings and laboratory values; had not
`used esomeprazole for the previous 8 weeks, any
`prescribed medication for the previous 2 weeks, or
`over-the-counter drugs (including herbal remedies,
`vitamins and minerals) in the week preceding the
`first dose of study drug; were not using anabolic
`
`steroids; were not of childbearing potential or lactat-
`ing; had no history of cardiac, renal, hepatic, neuro-
`logical or significant gastrointestinal diseases; had
`not donated blood in the 12 weekspriorto the first
`dose of study drug or during the study; did not
`smoke or consume any other sort of nicotine (or
`equivalent); and were not using concomitant medi-
`cations (except nasal spray for nasal congestion, or
`paracetamol).
`The studies (study codes: SH-Nen-0016 and SH-
`Nen-0017) were conducted in accordance with the
`Declaration of Helsinki and were approved by the
`ethics committee of the University of Uppsala and
`by the Swedish Medical Products Agency. Written
`informed consent was received from all subjects
`prior to participation. The studies were performedat
`Quintiles AB, Uppsala, Sweden.
`All subjects underwent a full clinical examina-
`tion, physical examination and electrocardiogram
`(ECG) at pre-entry. A laboratory screen for
`haematology and serum biochemistry was per-
`formed prior to enrolment, on day 7 of each treat-
`ment period, and 5-7 daysafter the last study day.
`
`Study Design
`
`The two studies were conducted according to a
`randomised, open, three-way crossover design. Each
`of the three treatment periods lasted for 7 days,
`which wassufficient to achieve steady state. The
`subjects received either oral doses of an eso-
`meprazole 40mg capsule once daily (studies A and
`B), a naproxen 250mgtablet twice daily (study A), a
`rofecoxib 12.5mg tablet once daily (study B), or
`esomeprazole in combination with naproxen (study
`A) or rofecoxib (study B). Each treatment period
`was separated by a washout period of at
`least
`14 days. Blood samples for determination of eso-
`meprazole, naproxen and rofecoxib were taken for
`24 hours post-dose on the last day of each treatment
`period. Alcohol was not allowed from 2 days before
`pre-entry, during each treatment period, and be-
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
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`

`734
`
`Hassan-Alin etal.
`
`tween the last study day and the follow-up visit.
`Drugs available on prescription were not allowed
`during the last 2 weeks preceding the studies and
`during the studies.
`On the investigational days, the subjects arrived
`at the study centre in the morning, having fasted
`since the previous evening, for administration of the
`study drug andcollection of repeated blood samples.
`On these days, standardised meals were served
`4 dunch), 6 (light meal), 10 (dinner) and 13 (light
`meal) hours after drug administration.
`
`Study Drugs
`
`the subjects received an eso-
`In study A,
`meprazole 40mg capsule (Nexium®, AstraZeneca
`Tablet Production, Sweden)! once daily, a naproxen
`250mg tablet
`(Naprosyn®, Roche, Switzerland)
`twice daily, or a combination of the two drugsorally
`for 7 days. In study B, the subjects received an
`esomeprazole capsule (Nexium®) once daily, a
`rofecoxib 12.5mg tablet (Vioxx®, MSD, Germany)
`once daily, or a combination of the two drugsorally
`for 7 days.
`
`Blood Sampling and Bioanalytical Methods
`
`for assay of esomeprazole,
`Blood samples
`naproxen and rofecoxib were taken at pre-dose and
`at 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3,
`3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 20 and 24 hours
`following drug administration on day 7. The blood
`samples were drawn from an indwelling cannula in a
`forearm vein and collected in heparinised tubes,
`centrifuged and the plasma transferred, frozen and
`stored until analysis.
`The plasma concentration of esomeprazole was
`analysed using normalphase liquid chromatography
`with ultraviolet detection.22! The limit of quantifica-
`tion (LOQ) for this method is 25 nmol/L with a
`coefficient of variation (CV) of <20%. The plasma
`
`concentration of naproxen was determined using
`liquid chromatography and fluorescence detection.
`The flow rate was 0.5 mL/min and the injection
`volume was 20-40uUL. The retention time was
`3.0 minutes and absolute recovery in the concentra-
`tion range of 0.5-500 mol/L was between 89% and
`100%. The LOQ was0.5 umol/L (CV <20%). Intra-
`and interassay repeatability were 4-5% and 46%,
`respectively. Rofecoxib plasma concentration was
`also determined using liquid chromatography and
`fluorescence detection. The flow rate was 1.2 mL/
`
`min and the injection volume was 150uL. Thereten-
`tion time was 4.5 minutes and the absolute recovery
`in the concentration range of 3.0—200 nmol/L was
`between 90% and 91%. The LOQ was 1.5 nmol/L
`(CV <20%). Both intra- and interassay repeatability
`were 6—-7%. The plasma samples were analysed for
`esomeprazole, naproxen and rofecoxib at Quin-
`tiles AB, Uppsala, Sweden.
`
`Pharmacokinetic and Statistical Analyses
`
`Pharmacokinetic parameters of esomeprazole,
`naproxen and rofecoxib were estimated by non-
`compartmental analysis using WinNonlin computer
`software. The area under the plasma concentration
`versus time curve during the dosing interval (AUC+)
`wascalculated according to a log-linear trapezoidal
`method. For naproxen, the AUC; wascalculated up
`to 12 hours post-dose, while for esomeprazole and
`rofecoxib the AUC, wascalculated up to 24 hours
`post-dose. The elimination rate constant (A) was
`determined by log-linear regression analysis of the
`terminal slope of at least the last three plasma con-
`centration versus time points. The terminal plasma
`elimination half-life (ty.) was calculated as 1n2/A.
`The observed maximum plasma concentration
`(Cmax) and the time to reach Cmax (tmax) were also
`recorded.
`
`1 The useof trade namesis for product identification purposes only and does not imply endorsement.
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
`
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`

`

`No Pharmacokinetic Interaction between Esomeprazole and Naproxen/Rofecoxib
`
`735
`
`The pharmacokinetic parameters were analysed
`using
`a mixed-model
`analysis
`of
`variance
`(ANOVA)with fixed effects for sequence, period
`and treatment(the drug alone or in combination) and
`a random effect for subjects within sequences. The
`pharmacokinetic parameters were log-transformed
`prior to the analysis. Estimates and 95% confidence
`limits of the log-transformed parameters were anti-
`logarithmised, and the results are presented as geo-
`metric means and ratios with 95% confidenceinter-
`
`vals (CIs). The median was presented for tmax.
`
`Results
`
`Thirty-two healthy subjects (13 males and 19 fe-
`males) with a mean age of 24 years and a mean
`bodyweight of 69kg participated in the eso-
`meprazole and naproxen study (study A). Thirty-one
`subjects completed the treatment comparison ofes-
`omeprazole alone and in combination with naprox-
`en, while 30 subjects completed the treatment com-
`parison of naproxen alone and in combination with
`esomeprazole.
`Thirty-two healthy subjects (15 males and 17 fe-
`males) with a mean age of 26 years and a mean
`weight of 69kg participated in the esomeprazole and
`rofecoxib study (study B). Twenty-eight subjects
`completed the
`treatment
`comparison of eso-
`meprazole alone and in combination with rofecoxib,
`
`while 30 subjects completed the treatment compari-
`son of rofecoxib alone and in combination with
`
`esomeprazole.
`All those who withdrew before the end of the
`
`study did so for personal reasons. There were no
`safety issues.
`
`Esomeprazole and Naproxen
`
`Median tmax values following administration of
`esomeprazole, naproxen and the combination are
`presentedin table I. Estimates of the pharmacokinet-
`ic parameters with 95% CIs for esomeprazole and
`naproxen andthe ratios with 95% Cls of the parame-
`ters are presented in table II andtable III, respective-
`ly. The mean plasma concentration-time cuves are
`shown in figure 1 and figure 2.
`Both esomeprazole and naproxen were rapidly
`absorbed, and the median tmax was approximately
`1.5 hours for both drugs, both during monotherapy
`and during combination therapy (table I and
`figures 1 and 2). No changes were observed in
`AUC, Cmax and t% for esomeprazole after co-ad-
`ministration with naproxen compared with eso-
`meprazole monotherapy (see table ID. The ratios
`(combination/esomeprazole
`alone)
`for AUCz,
`Cmax and t', were 0.96, 0.92 and 1.02, respectively,
`as shown in table III. For naproxen, the AUCz,
`Cmax and ty, after co-administration with eso-
`
`Minimum (h)
`
`Maximum (h)
`
`Table I. Median time to the observed maximum plasma concentration (tmax) with minimum and maximum values following monotherapy
`with esomeprazole 40mg once daily, naproxen 250mg twice daily, rofecoxib 12.5mg once daily and a combination of esomeprazole with
`naproxen or rofecoxib for 7 days in healthy male and female subjects
`Treatment
`Median (h)
`Study A
`Esomeprazole alone (n = 31)
`Naproxen alone (n = 31)
`Esomeprazole with naproxen (n = 31)
`Naproxen with esomeprazole (n = 30)
`Study B
`Esomeprazole alone (n = 28)
`Rofecoxib alone (n = 30)
`Esomeprazole with rofecoxib (n = 28)
`Rofecoxib with esomeprazole (n = 30)
`
`1.50
`1.50
`1.75
`1.50
`
`1.50
`2.88
`1.50
`3.00
`
`1.00
`0.75
`1.00
`0.50
`
`1.00
`1.75
`0.75
`1.25
`
`2.75
`4.00
`4.00
`4.50
`
`3.50
`4.50
`3.50
`4.50
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
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`DRL EXHIBIT 1016 PAGE 5
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`

`

`736
`
`Hassan-Alin etal.
`
`45
`4.0
`
`—} Esomeprazole alone
`—L- Esomeprazole with naproxen
`
`
`
`
`
`—L} Naproxenalone
`—HL Naproxenwith esomeprazole
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`
`
`
`
`
`
`Meanplasmaconcentration(mol/L)
`
`
`
`
`
`
`
` 0 5 10 15 20 25 30
`
`
`
`
`
`
`Time after dose (h)
`Fig. 2. Mean plasma concentration of naproxen following repeated
`oral administration of a naproxen 250mgtablet twice daily alone
`and in combination with an esomeprazole 40mg capsule once daily
`for 7 days in healthy male and female subjects (n = 30).
`
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Meanplasmaconcentration(mol/L) 0
`
`meprazole were similar to those after treatment with
`naproxen alone (see table II). The ratios (combina-
`tion/naproxen alone) for AUC+z, Cmax and ty, were
`
`Time after dose (h)
`Fig. 1. Mean plasma concentration of esomeprazole following re-
`peated oral administration of an esomeprazole 40mg capsule once
`daily alone and in combination with a naproxen 250mgtablet twice
`daily for 7 days in healthy male and female subjects (n = 31).
`
`0.98, 1.00 and 0.96, respectively, as shown in ta-
`ble III.
`
`Table Il. Geometric means and 95% Cls of the area under the plasma concentration vs time curve during the dosinginterval (AUC,), the
`observed maximum plasma concentration (Cmax) and the terminal plasmaelimination half-life (ty.) of esomeprazole and naproxenfollowing
`repeated oral administration of an esomeprazole 40mg capsule oncedaily (A), a naproxen 250mgtablettwice daily (B), or a combination of
`an esomeprazole 40mg capsule once daily and a naproxen 250mgtablettwice daily (C), for 7 days in healthy male and female subjects
`Treatment
`Geometric mean
`95% Cl
`
`Esomeprazole (n = 31)
`AUC (umole h/L)
`Esomeprazole with naproxen (C)
`Esomeprazole alone (A)
`Cmax (mol/L)
`Esomeprazole with naproxen (C)
`Esomeprazole alone (A)
`t% (h)
`Esomeprazole with naproxen (C)
`Esomeprazole alone (A)
`Naproxen (n = 30)
`AUC (umole h/L)
`Naproxen with esomeprazole (C)
`Naproxen alone (B)
`Cmax (umol/L)
`Naproxen with esomeprazole (C)
`Naproxen alone (B)
`fe (h)
`Naproxen with esomeprazole (C)
`Naproxen alone (B)
`
`12.22
`12.75
`
`4.52
`4.90
`
`1.39
`1.36
`
`2530.7
`2594.2
`
`327.24
`326.16
`
`12.90
`13.47
`
`10.61, 14.07
`11.07, 14.69
`
`4.06, 5.03
`4.40, 5.45
`
`1.29, 1.50
`1.26, 1.46
`
`2420.4, 2646.1
`2481.0, 2712.5
`
`313.28, 341.82
`312.25, 340.69
`
`12.41, 13.41
`12.96, 14.01
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
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`DRL EXHIBIT 1016 PAGE 6
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`

`

`No Pharmacokinetic Interaction between Esomeprazole and Naproxen/Rofecoxib
`
`737
`
`45
`40
`
`—{1- Esomeprazole alone
`—f-— Esomeprazole with rofecoxib
`
`
`
`
`
`
`
`Meanplasmaconcentration(mol/L) 0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`TableIll. Ratios of the geometric means and 95% Cls of the area
`under the plasma concentration vs time curve during the dosing
`interval
`(AUC;),
`the observed maximum plasma concentration
`(Cmax) and the terminal plasma elimination half-life (ty) of es-
`omeprazole and naproxen. Values relate to a combination of an
`esomeprazole 40mg capsule once daily and a naproxen 250mg
`tablet twice daily, divided by those following administration of an
`esomeprazole 40mg capsule once daily (n = 31) or a naproxen
`250mgtablet twice daily (n = 30) for 7 days in healthy male and
`female subjects.
`Treatment
`Esomeprazole (n = 31)
`AUC,(C/A)
`Cmax (C/A)
`ty, (C/A)
`Naproxen (n = 30)
`0.94, 1.01
`0.98
`AUC, (C/B)
`0.97, 1.04
`1.00
`Cmax (C/B)
`0.93, 0.99
`0.96
`ty. (C/B)
`A = esomeprazole, B = naproxen; C = esomeprazole/naproxen
`combination.
`
`0.96
`0.92
`1.02
`
`0.89, 1.03
`0.85, 1.00
`0.98, 1.07
`
`Estimate
`
`95% Cl
`
`Median tmax values following esomeprazole,
`rofecoxib and the combination are presented in ta-
`ble I. Estimates of the pharmacokinetic parameters
`with 95% CIs for esomeprazole and rofecoxib are
`presented
`in
`table
`IV. The
`ratios
`of
`the
`pharmacokinetic parameters with 95% CIs are
`presented in table V. The mean plasmaconcentra-
`tion-time curves are shownin figure 3 and figure 4.
`
`Esomeprazole was rapidly absorbed with a tmax
`of 1.5 hours, while the median tmax for rofecoxib
`was approximately 3 hours, both with rofecoxib
`alone and in combination with esomeprazole (ta-
`ble I. The AUC;, Cmax and ty for esomeprazole
`were not affected by rofecoxib (table IV). Theratios
`(combination/esomeprazole alone) for AUC, Cmax
`and ty, were 1.05, 1.05 and 0.99, respectively, as
`shown in table V. For rofecoxib, there wasa slight
`increase in AUC, and Cmax after co-administration
`with
`esomeprazole
`compared with rofecoxib
`monotherapy (table IV). The ratios (combination/
`rofecoxib alone) for AUC, Cmax and ty, were 1.15,
`1.14 and 1.06, respectively, as shown in table V.
`
`Time after dose (h)
`Fig. 3. Mean plasma concentration of esomeprazole following re-
`peated oral administration of an esomeprazole 40mg capsule once
`daily alone and in combination with a rofecoxib 12.5mg tablet once
`daily for 7 days in healthy male and female subjects (n = 28).
`
`Esomeprazole and Rofecoxib
`
`Discussion
`
`Esomeprazole is expected to be widely used in
`the managementof upper GI symptoms, and to heal
`and prevent gastric and duodenal ulcers associated
`eso-
`with continued NSAID use. Therefore,
`meprazole will commonly be used in combination
`with NSAIDs. Although it seemslikely that in most
`
`900
`
`—L} Rofecoxib alone
`—- Rofecoxib with esomeprazole
`
`800
`
`700
`
`600
`
`
`
`500
`
`400
`
`300
`
`200
`
`
`
`
`
`Meanplasmaconcentration(umol/L) 100
`
` 0 5 10 15 20 25 30
`
`
`
`
`
`
`
`
`
`
`
`
`Timeafter dose (h)
`Fig. 4. Mean plasma concentration of rofecoxib following repeated
`oral administration of a rofecoxib 12.5mg tablet once daily alone
`and in combination with an esomeprazole 40mg capsule once daily
`for 7 days in healthy male and female subjects (n = 30).
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
`
`DRL EXHIBIT 1016 PAGE 7
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`

`738
`
`Hassan-Alin etal.
`
`Table IV. Geometric means and 95% Cls of the area under the plasma concentration vs time curve during the dosing interval (AUC;), the
`observed maximum plasma concentration (Cmax) and the terminal plasmaelimination half-life (ty) of esomeprazole and rofecoxib following
`repeated oral administration of an esomeprazole 40mgcapsule oncedaily (A), a rofecoxib 12.5mgtablet once daily (B), or a combination of
`an esomeprazole 40mg capsule once daily and a rofecoxib 12.5mg tablet once daily (C) for 7 days in healthy male and female subjects
`Treatment
`Geometric mean
`95% Cl
`
`Esomeprazole (n = 28)
`AUC (umol® h/L)
`Esomeprazole with rofecoxib (C)
`Esomeprazole alone (A)
`Cmax (umol/L)
`Esomeprazole with rofecoxib (C)
`Esomeprazole alone (A)
`f% (h)
`Esomeprazole with rofecoxib (C)
`Esomeprazole alone (A)
`Rofecoxib (n = 30)
`AUC (umol ® h/L)
`Rofecoxib with esomeprazole (C)
`Rofecoxib alone (B)
`Cmax (umol/L)
`Rofecoxib with esomeprazole (C)
`Rofecoxib alone (B)
`th (h)
`Rofecoxib with esomeprazole (C)
`Rofecoxib alone (B)
`
`12.57
`11.99
`
`4.88
`4.63
`
`1.39
`1.41
`
`9.61
`8.36
`
`0.89
`0.78
`
`12.91
`12.17
`
`cases the NSAIDin question will be a non-selective
`agent, use of COX-2-selective agents has not been
`tuled out, and certain patients maystill benefit from
`
`10.47, 15.10
`9.98, 14.40
`
`4.18, 5.70
`3.96, 5.41
`
`1.25, 1.56
`1.26, 1.57
`
`8.37, 11.04
`7.28, 9.61
`
`0.78, 1.01
`0.68, 0.88
`
`11.58, 14.40
`10.91, 13.58
`
`these agents. The aim of the present study was to
`tule out any potential for drug-drug interaction be-
`tween esomeprazole and naproxen, being a repre-
`sentative non-selective NSAID,and rofecoxib, as an
`example of a COX-2-selective NSAID.
`
`Esomeprazole plasmalevels were not affected by
`naproxen or rofecoxib. The AUC;, Cmax and ty, for
`esomeprazole after co-administration with naproxen
`or
`rofecoxib were similar
`to those after eso-
`
`Table V. Ratios of the geometric means and 95% Cls of the area
`under the plasma concentration vs time curve during the dosing
`interval
`(AUC;),
`the observed maximum plasma concentration
`(Cmax) and the terminal plasma elimination half-life (ty). Values
`relate to a combination of an esomeprazole 40mg capsule once
`daily and a rofecoxib 12.5mg tablet once daily, divided by those
`following administration of an esomeprazole 40mg capsule once
`daily (n = 28) or a rofecoxib 12.5mg tablet once daily (n = 30)in
`healthy male and female subjects
`Treatment
`Estimate
`
`95% Cl
`
`meprazole alone. The AUCz, Cmax and ty, of naprox-
`en after co-administration with esomeprazole were
`similar to those after naproxen alone. There was a
`Esomeprazole (n = 28)
`marginal increase in AUC, and Cmax for rofecoxib
`0.96, 1.15
`1.05
`AUC;(C/A)
`0.94, 1.18
`1.05
`Cmax (C/A)
`during the combination therapy compared with
`0.90, 1.08
`0.99
`ty, (C/A)
`
`rofecoxib The—slightadministered alone.
`
`
`Rofecoxib (n = 30)
`pharmacokinetic changes seen would not be ex-
`1.06, 1.24
`1.15
`AUC;(C/B)
`pected to have anyclinical relevance. Rofecoxib has
`1.02, 1.28
`1.14
`Cmax (C/B)
`double plasma concentration-time profiles when ad-
`0.97, 1.16
`1.06
`ty. (C/B)
`ministered alone”?! and in combination with es-
`A = esomeprazole; B = rofecoxib; C = esomeprazole/rofecoxib
`combination.
`omeprazole (figure 4). This may be dueto redistri-
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
`
`DRL EXHIBIT 1016 PAGE 8
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`

`

`No Pharmacokinetic Interaction between Esomeprazole and Naproxen/Rofecoxib
`
`739
`
`bution or to an enterohepatic circulation phenome-
`non. We do not know the reason(s) for the double
`profile for rofecoxib; however,
`this is a normal
`concentration-time profile for rofecoxib.23]
`Pharmacokinetics is one of the factors that may
`influence the NSAID safety profile. Although the
`majority of marketed NSAIDs are well absorbed,
`metabolised extensively, subject to fairly minimal
`first-pass extraction, and have linear pharmacokinet-
`ics, some more subtle differences are apparent.“
`Esomeprazole metabolism is mediated by cyto-
`chrome P450 (CYP)
`isoforms, CYP2C19 and
`CYP3A4,25] while the NSAIDs have been shown to
`be mainly metabolised by another CYP isoform,
`CYP2C9.6l On thebasis of this knowledge, a drug
`interaction would not be expected between eso-
`meprazole and the NSAIDs. However, a recently
`published study has reported that the extent of the
`role of CYP2C9in the overall clearance of different
`
`NSAIDsis varied, and that CYP3A4 activity can
`sometimes be involved.™! Wefeel that a lack of
`drug interactions during combination therapy with
`esomeprazole andall available NSAIDs should not
`be assumed, but rather evaluated on an individual
`basis. The results of the present interaction study
`help to confirm that drug-drug interactions are not
`an issue between esomeprazole and naproxen or
`rofecoxib. This study is also in agreement with
`previous
`studies
`involving omeprazole, which
`showed
`no
`drug-drug
`interactions
`between
`omeprazole and three different NSAIDs (naproxen,
`diclofenac or piroxicam).271
`
`Conclusion
`
`Neither naproxen nor rofecoxib have any effect
`on the pharmacokinetics of esomeprazole, and eso-
`meprazole does not have any effect on the
`pharmacokinetics of naproxen or rofecoxib. The
`clinical implications of these findings are that eso-
`meprazole can be used together with naproxen or
`rofecoxib without pharmacokinetic drug interaction
`
`safety concerns for the healing and prevention of
`gastric and duodenal ulcers in patients needing con-
`tinuous NSAID treatment to relieve inflammation
`
`and pain. Repeated oral administration of eso-
`meprazole alone, as well as in combination with
`naproxen or rofecoxib, was well tolerated.
`
`Acknowledgements
`
`The study was sponsored by AstraZeneca R&D Mélndal,
`Mélndal, Sweden.
`
`References
`1. Retail & Provider Perspective, National Prescription Audit,
`1999-2000. Plymouth (PA): IMS Health, 2000
`2. Wolfe F, Kleinheksel SM, Spitz PW,et al. A multicentre study
`ofhospitalization in rheumatoid arthritis: frequency, medical-
`surgical admissions, and charges. Arthritis Rheum 1986; 29:
`614-9
`3. Hazleman BL.Incidence of gastropathy in destructive arthropa-
`thies. Scand J Rheumatol Suppl 1989; 78: 1-4
`4. Griffin MR. Epidemiology of nonsteroidal anti-inflammatory
`drug-associated gastroduodenal injury. Am J Med 1998; 104
`(3A): 238-98
`5. Hirschowitz BI. Non-steroidal anti-inflammatory drugs and the
`gastrointestinal tract. Gastroenterologist 1994; 2: 207-23
`6. Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic
`ulcers. BMJ 1990; 300: 278-84
`7. Myerson RM. NSAID-associated gastroduodenal damage. J
`Pharm Med 1992; 2: 277-84
`8. Singh G. Recent considerations in nonsteroidal anti-inflam-
`matory drug gastropathy. Am J Med 1998; 105 (1B): 31S-8S
`9. Bombardier C, Laine L, Reicin A, et al. VIGOR Study Group.
`Comparison of upper gastrointestinal toxicity of rofecoxib and
`naproxen in patients with rheumatoid arthritis. N Engl J Med
`2000; 343: 1520-8
`10. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal
`toxicity with celecoxib vs nonsteroidal anti-inflammatory
`drugs for osteoarthritis and rheumatoid arthritis. The CLASS
`Study: a randomized controlled trial. JAMA 2000; 284:
`1247-55
`11. Lenzer J. Pfizer is asked to suspend sales of painkiller [news
`item]. BMJ 2005; 330: 862
`12. Young D. FDA ponders future of NSAIDS: Pfizer reluctantly
`withdraws Bextra. Am J Health Syst Pharm 2005; 62:
`997-1000
`13. US Food and Drug Administration. COX-2 selective (includes
`Bextra, Celebrex and Vioxx) and non-selective non-selectivel
`non-steroidal anti-inflammatory drugs (NSAIDs)
`[online].
`Available from URL: http://www.fda.gov/cder/drg/infopage/
`cox2/ [Accessed 2005 Sep 5]
`14. European Medicines Agency Post-authorisation of Medicines
`for Human Use. Questions and answers on celecoxib/COX-2
`inhibitors
`[online]. Available
`from URL:
`http://ww-
`
`© 2005 Adis Data Information BV.All rights reserved.
`
`Clln Drug Invest 2005; 25 (11)
`
`DRL EXHIBIT 1016 PAGE 9
`
`DRL EXHIBIT 1016 PAGE 9
`
`

`

`740
`
`Hassan-Alin et al.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`w.emea.eu.int/pdfs/human/press/pr/21074505en.pdf
`cessed 2005 Sep 5]
`Kuehn BM. FDApanel: keep COX-2 drugs on market: black
`box for COX-2 labels, caution urged for all NSAIDs. JAMA
`2005; 292: 1571-2
`
`[Ac-
`
`Young D. FDA labors over NSAID decisions: panel suggests
`COX-2 inhibitors stay available. Am J Health Syst Pharm
`2005; 62: 668-72
`
`Murray S. Health Canada lukewarm on Vioxx panel findings
`[news item]. CMAJ 2005; 173: 350
`
`Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of
`omeprazole with ranitidine for ulcers associated with non-
`steroidal anti-inflammatory drugs. N Engl J Med 1998; 338:
`719-26
`
`Hawkey CJ, Karrasch JA, Szczepaiiski L, et al. Omeprazole
`compared with misoprostol for ulcers associated with non-
`steroidal anti-inflammatory drugs. N Engl J Med 1998; 338:
`727-34
`
`Elliott SL, Ferris RJ, Giraud AS,et al. Indomethacin damage to
`rat gastric mucosa is markedly dependent on luminal pH. Clin
`Exp Pharmacol Physiol 1996; 23: 432-4
`Rohss K, Wilder-Smith C, Claar-Nilsson C,et al. Esomeprazole
`40mg provides more effective acid control than standard doses
`of all other proton pump inhibitors [abstract]. Gut 2001; 49
`Suppl. III: 2649
`Lagerstrém PO,Persson BA. Determination of omeprazole and
`metabolites in plasma and urine by liquid chromatography. J
`Chromatogr 1984; 309: 347-56
`
`23. Davies NM, Teng XW, Skjodt NM. Pharmacokinetics of
`rofecoxib:
`Clin
`a specific cyclo-oxygenase-2 inhibitor.
`Pharmacokinet 2003; 42: 545-56
`
`24. Rodrigues AD. Impact of CYP2C9 genotype on pharmacokinet-
`ics: are all cyclooxygenase inhibitors the same? Drug Metab
`Dispos 2005, Aug 23; [Epub ahead ofprint]
`25. Abelé A, Andersson TB, Antonsson M,et al. Stereoselective
`metabolism of omeprazole by human cytochrome P450 en-
`zy