ORIGINAL RESEARCH ARTICLE
`
`Clln Drug Invest 2005.- 25 (1 1): 731-740
`1173-2563/05/0011-0731/534.95/0
`© 2005 Adls Dara Informatlon 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,1]. Naesdal,1 C. Nilsson-Pieschl,1 G. Lai’ngstriim1 and T. Andersson2
`
`1 AstraZeneca R&D Molndal, Molndal, Sweden
`
`2 AstraZeneca LP, Wilmington, Delaware, USA
`
`Abstract
`
`Background: We investigated the potential interactions between esomeprazole
`and a non-selective nonsteroidal anti-inflammatory drug (NSAID; naproxen) or a
`cyclo-oxygenase (COX)-2-se1ective NSAID (rofecoxib) in healthy subjects.
`
`Methods: Two studies 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 once daily (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 washout period.
`
`Results: On day 7 of dosing, the ratios (and 95% CIs) for the area under the
`plasma concentration-time curve during the dosing interval (AUCT) 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 AUC1: and cm 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 phannacokinetics of naproxen or rofecoxib.
`These findings indicate that esomeprazole can be used in combination with
`NSAIDs without the risk of a phannacokinetic interaction.
`
`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 1
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 1
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`

`

`732
`
`Hassun—Alin et a1.
`
`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
`
`NSAIDsI” The use of NSAIDs is 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 NSAIDs are, however, associated with a sub-
`stantial number of adverse events, with non-selec-
`
`tive NSAIDs accounting for 20% and 25% of all
`reported adverse drug events in the UK and US,
`
`respectively.[2'3] NSAID-associated upper gastro-
`intestinal (GI) tract adverse effects range from dys-
`peptic symptoms to peptic ulceration and ulcer com-
`
`plications.[41 Some 15—40% of NSAID users report
`upper GI symptomsls] and 10—30% of long-term
`NSAID users will develop a peptic ulcer, predomi-
`
`nantly in the stomach.[5’7] NSAID use increases 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.[41
`It has been estimated that
`there are over
`
`and
`year
`per
`admissions
`hospital
`100 000
`16 500 deaths per year due to NSAID-induced GI
`
`complications in the US.[8]
`
`The anti-inflammatory properties of NSAIDs are
`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,
`was that treatment with rofecoxib was associated
`
`with significantly fewer upper GI events than treat-
`
`ment with naproxen.[9] Celecoxib was compared
`with ibuprofen and diclofenac in a similar study.
`
`The armual 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 (S325 mg/day) aspirin negated the GI
`
`advantage of celecoxib.[1°] It is also worth noting
`that in this trial, the doses of celecoxib used were
`2—4 times the maximum recommended doses for the
`
`treatment of RA and 0A.
`
`Unfavourable cardiovascular risk data has led
`
`to an urgent
`
`re-evaluation of the use of the
`
`COX-2—selective class of NSAIDs in clinical prac-
`
`tice, culminating in the market suspension of the
`COX-2—selective agents rofecoxib and valdecox—
`
`ib.[1 1’12] The US FDA has requested 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-se1ective agents to the lowest
`
`practical dose for the most urgent caseslm 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.[141 Celecox-
`ib is still available in the US, and celecoxib and
`
`various other COX-2—selective agents are still avail-
`
`able in Europe.[13-14] Additionally, during the first
`quarter of 2005, an FDA advisory panel recom-
`
`mended that rofecoxib should again be made availa-
`ble to patients, and that black-box warnings be
`placed on the labels of all COX-2—selective
`
`agents.[15’16] Canadian health authorities may also be
`moving towards approving the return of rofecoxib to
`
`it does seem likely
`the market.“71 Consequently,
`that,
`in the future, a range of COX-2—selective
`
`© 2005 Adls Data Informatlon BV. All rlghts reserved.
`
`Clln Drug Invest 2005; 25 (1 1)
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 2
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 2
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`

`

`No Pharrnacokinetic Interaction between Esomeprazole and Naproxen/Rofecoxib
`
`733
`
`agents may still have a role to play in the effective
`management of certain patients with low cardiovas-
`cular risk.
`
`The proton pump inhibitor (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 NSAID treatrnent.[18:19] The degree
`of gastric damage caused by NSAIDs is highly
`
`dependent on intragastric pH.[18’2°] Esomeprazole,
`which confers a longer time with intragastric pH >4
`than all other PPIs,[21] is expected to be effective for
`the prevention of NSAID-associated ulcers.
`
`As esomeprazole is expected to be widely used in
`the healing and prevention of gastric and duodenal
`ulcers, and to control upper GI symptoms in patients
`needing continuous NSAID treatment to 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 may still 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
`frrst 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 weeks prior to 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 performed at
`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 enrohnent, on day 7 of each treat-
`ment period, and 5—7 days after 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 was sufficient to achieve steady state. The
`subjects received either oral doses of an eso-
`meprazole 40mg capsule once daily (studies A and
`B), a naproxen 250mg tablet 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 Adls Data Informotlon BV. All rlghts reseNed.
`
`Clln Drug Invest 2005; 25 (11)
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 3
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 3
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`

`

`734
`
`Hassun—Alin et a1.
`
`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 and collection of repeated blood samples.
`On these days, standardised meals were served
`4 (lunch), 6 (light meal), 10 (dinner) and 13 (light
`meal) hours after drug administration.
`
`Study Drugs
`
`In study A,
`
`the subjects received an eso-
`
`meprazole 40mg capsule (Nexium®, AstraZeneca
`Tablet Production, Sweden)1 once daily, a naproxen
`250mg tablet
`(Naprosyn®, Roche, Switzerland)
`twice daily, or a combination of the two drugs orally
`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 drugs orally
`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.
`
`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—40uL. The retention time was
`
`3.0 minutes and absolute recovery in the concentra-
`
`tion range of 0.5—500 umol/L was between 89% and
`100%. The LOQ was 0.5 umollL (CV 520%). Intra-
`
`and interassay repeatability were 4—5% and 4—6%,
`
`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. The reten-
`tion time was 4.5 minutes and the absolute recovery
`
`in the concentration range of 30—200 nmol/L was
`between 90% and 91%. The LOQ was 1.5 nmol/L
`
`(CV 320%). 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-
`
`compartrnental analysis using WinNonlin computer
`software. The area under the plasma concentration
`
`versus time curve during the dosing interval (AUCT)
`
`was calculated according to a log-linear trapezoidal
`
`method. For naproxen, the AUCT was calculated up
`
`to 12 hours post-dose, while for esomeprazole and
`rofecoxib the AUCT was calculated up to 24 hours
`
`post-dose. The elimination rate constant Or.) was
`determined by log-linear regression analysis of the
`terminal slope of at least the last three plasma con-
`
`The plasma concentration of esomeprazole was
`analysed using normal phase liquid chromatography
`
`centration versus time points. The terminal plasma
`elimination half-life (tI/z) was calculated as ln2/k.
`
`with ultraviolet detectionm] The limit of quantifica-
`tion (LOQ) for this method is 25 nmol/L with a
`
`coefficient of variation (CV) of <20%. The plasma
`
`The observed maximum plasma concentration
`(Cmax) and the time to reach Cmax (tmax) were also
`recorded.
`
`1 The use of trade names is for product identification purposes only and does not imply endorsement.
`
`© 2005 Adls Data Information BV. All rights reserved.
`
`Clln Drug Invest 2005; 25 (l l)
`
`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 4
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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 % confidence inter-
`
`vals (C15). 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 of es—
`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 ond Naproxen
`
`Median tmax values following administration of
`esomeprazole, naproxen and the combination are
`presented in table I. Estimates of the pharmacokinet—
`ic parameters with 95% C1s for esomeprazole and
`naproxen and the ratios with 95 % CIs of the parame-
`ters are presented in table II and table 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
`AUCT, Cmax and tl/2 for esomeprazole after co-ad-
`ministration with naproxen compared with eso—
`
`meprazole monotherapy (see table II). The ratios
`(combination/esomeprazole
`alone)
`for AUCT,
`
`Cmax and W2 were 0.96, 0.92 and 1.02, respectively,
`as shown in table 111. For naproxen, the AUCT,
`Cmax and W2 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)
`Ftofecoxib 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 Adls Data Information BV. All rights reseNed.
`
`Clln Drug Invest 2005; 25 (l l)
`
`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 5
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 5
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`

`

`736
`
`Hassan—Alin et a1.
`
`—|:l— Naproxen alone
`+ Naproxen with esomeprazole
`
`4'5
`4 0
`
`—l:l— Esomeprazole alone
`+ Esomeprazole with naproxen
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`
`
`Meanplasmaconcentration(pmol/L)
`
`
`
`
`
`
`
`
`
`
`
`
`
` 0 5 1O 15 20 25 30
`
`
`
`
`Time after dose (h)
`Fig. 2. Mean plasma concentration of naproxen following repeated
`oral administration of a naproxen 250mg tablet twice daily alone
`and in combination with an esomeprazole 40mg capsule once daily
`for 7 days in healthy male and female subjects (n = 30).
`
`
`
`
`
`Meanplasmaconcentration(pmol/L)
`
`
`
`0
`
`5
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`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 250mg tablet twice
`daily for 7 days in healthy male and female subjects (n = 31).
`
`meprazole were similar to those after treatment with
`naproxen alone (see table II). The ratios (combina-
`tion/naproxen alone) for AUCT, Cmax and tl/2 were
`
`0.98, 1.00 and 0.96, respectively, as shown in ta-
`ble III.
`
`Table II. Geometric means and 95% Cls of the area under the plasma concentration vs time curve during the dosing interval (AUC1), the
`observed maximum plasma concentration (Cmax) and the terminal plasma elimination half-life (tvz) of esomeprazole and naproxen following
`repeated oral administration of an esomeprazole 40mg capsule once daily (A), a naproxen 250mg tablet twice daily (B), or a combination of
`an esomeprazole 40mg capsule once daily and a naproxen 250mg tablet twice daily (C), for 7 days in healthy male and female subjects
`Treatment
`Geometric mean
`95% Cl
`
`Esomeprazole (n = 31)
`AUG: (pmol I h/L)
`Esomeprazole with naproxen (C)
`Esomeprazole alone (A)
`Cmax (pmoVL)
`Esomeprazole with naproxen (C)
`Esomeprazole alone (A)
`f’/2 (h)
`Esomeprazole with naproxen (C)
`Esomeprazole alone (A)
`Naproxen (n = 30)
`AUG: (pmol o h/L)
`Naproxen with esomeprazole (C)
`Naproxen alone (B)
`Cmax (pmoVL)
`Naproxen with esomeprazole (C)
`Naproxen alone (B)
`1% (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 Adls Data Information BV. All rights reserved.
`
`Clln Drug Invest 2005; 25(11)
`
`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 6
`
`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 6
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`

`

`No Pharmacokinetic Interaction between Esomeprazole and Naproxen/Rofecoxib
`
`737
`
`4'5
`4 0
`
`—|:l— Esomeprazole alone
`+ Esomeprazole with rofecoxib
`
`
`
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Table III. Ratios of the geometric means and 95% Cls of the area
`under the plasma concentration vs time cun/e during the dosing
`interval
`(AUCT),
`the observed maximum plasma concentration
`(Cmax) and the terminal plasma elimination half-life (ti/z) 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
`250mg tablet twice daily (n = 30) for 7 days in healthy male and
`female subjects.
`Treatment
`Esomeprazole (n = 31)
`AUCT (C/A)
`Crnax (CIA)
`1vz (CIA)
`Naproxen (n = 30)
`0.94, 1.01
`0.98
`AUCT (C/B)
`0.97, 1.04
`1.00
`Crnax (C/B)
`0.93, 0.99
`0.96
`I‘Iz (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 1. Estimates of the pharmacokinetic parameters
`
`with 95% C1s 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 plasma concentra-
`
`tion-time curves are shown in 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 1). The AUCT, Cmax and tl/2 for esomeprazole
`
`were not affected by rofecoxib (table IV). The ratios
`(combination/esomeprazole alone) for AUCT, Cmax
`
`and tl/2 were 1.05, 1.05 and 0.99, respectively, as
`
`shown in table V. For rofecoxib, there was a slight
`increase in AUCT and cm after co-admim'stration
`
`with
`
`esomeprazole
`
`compared with rofecoxib
`
`monotherapy (table IV). The ratios (combination/
`rofecoxib alone) for AUCT, Cmax and tl/2 were 1.15,
`
`1.14 and 1.06, respectively, as shown in table V.
`
`Meanplasmaconcentration(umollL)
`
`
`
`0
`
`Esomeprazole and Rofecoxib
`
`Discussion
`
`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 is expected to be widely used in
`the management of upper GI symptoms, and to heal
`and prevent gastric and duodenal ulcers associated
`650-
`with continued NSAID use. Therefore,
`
`meprazole will commonly be used in combination
`with NSAIDs. Although it seems likely that in most
`
`—|:l— Flofecoxib alone
`+ Flofecoxib with esomeprazole
`
`900
`
`800
`
`700
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`
`
`Meanplasmaconcentration(umol/L)
`
`
`
`
`
`
`
` 0 5 1 0 1 5 20 25 30
`
`
`
`
`
`
`
`
`
`
`Time after close (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 Adls Data Information BV. All rights reserved.
`
`Clln Drug Invest 2005; 25(11)
`
`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 7
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`

`

`738
`
`Hassan—Alin et al.
`
`Table IV. Geometric means and 95% Cls of the area under the plasma concentration vs time curve during the dosing interval (AUCT), the
`observed maximum plasma concentration (Cmax) and the terminal plasma elimination half-life (ti/z) of esomeprazole and rofecoxib following
`repeated oral administration of an esomeprazole 40mg capsule once daily (A), a rofecoxib 12.5mg tablet 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)
`AUG: (umol 0 h/L)
`Esomeprazole with rofecoxib (C)
`Esomeprazole alone (A)
`Cmax (umoVL)
`Esomeprazole with rofecoxib (C)
`Esomeprazole alone (A)
`1% (h)
`Esomeprazole with rofecoxib (C)
`Esomeprazole alone (A)
`Rofecoxib (n = 30)
`AUC1: (umol 0 h/L)
`Rofecoxib with esomeprazole (C)
`Rofecoxib alone (B)
`Cmax (umoVL)
`Rofecoxib with esomeprazole (C)
`Rofecoxib alone (B)
`1% (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 NSAID in question will be a non-selective
`agent, use of COX-2-selective agents has not been
`ruled out, and certain patients may still benefit from
`
`Table V. Ftatios of the geometric means and 95% Cls of the area
`under the plasma concentration vs time curve during the dosing
`interval
`(AUCT),
`the observed maximum plasma concentration
`(Cmax) and the terminal plasma elimination half-life (tvz). 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
`
`1.05
`1.05
`0.99
`
`Esomeprazole (n = 28)
`AUG: (C/A)
`Cmax (CIA)
`W; (C/A)
`Rofecoxib (n = 30)
`1.06, 1.24
`1.15
`AUG. (C/B)
`1.02, 1.28
`1.14
`Cmax (C/B)
`0.97, 1.16
`1.06
`W: (C/B)
`A = esomeprazole; B = rofecoxib; C = esomeprazole/rofecoxib
`combination.
`
`0.96, 1.15
`0.94, 1.18
`0.90, 1.08
`
`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
`rule 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 plasma levels were not affected by
`naproxen or rofecoxib. The AUCT, Cmax and tl/2 for
`esomeprazole after co-administration with naproxen
`or
`rofecoxib were similar
`to those after eso-
`
`meprazole alone. The AUCT, Cmax and tl/2 of naprox-
`en after co-administration with esomeprazole were
`similar to those after naproxen alone. There was a
`marginal increase in AUCT and Cmax for rofecoxib
`during the combination therapy compared with
`rofecoxib
`administered
`alone.
`The
`slight
`pharmacokinetic changes seen would not be ex-
`pected to have any clinical relevance. Rofecoxib has
`double plasma concentration-time profiles when ad-
`ministered alonem] and in combination with es-
`
`omeprazole (figure 4). This may be due to redistri-
`
`© 2005 Adls Data Information BV. All rights reserved.
`
`Clln Drug Invest 2005; 25(11)
`
`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 8
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`MYLAN PHARMS. INC. EXHIBIT 1016 PAGE 8
`
`

`

`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
`
`safety concerns for the healing and prevention of
`gastric and duodenal ulcers in patients needing con-
`tinuous NSAID treatment to relieve inflammation
`
`concentration-time profile for rofecoxib?“
`
`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,[251 while the NSAle have been shown to
`
`be mainly metabolised by another CYP isoform,
`
`CYP2C9.[26] On the basis 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 CYP2C9 in the overall clearance of different
`
`NSAIDs is varied, and that CYP3A4 activity can
`sometimes be involved.[7'4] We feel that a lack of
`
`drug interactions during combination therapy with
`esomeprazole and all 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).[27]
`
`Conclusion
`
`Neither naproxen nor rofecoxib have any effect
`on the pharrnacokinetics of esomeprazole, and eso-
`meprazole does not have any effect on the
`pharrnacokinetics 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
`
`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 Molndal,
`Molndal, Sweden.
`
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