FEBO 1 1995
`
`Effect of Perindopril on 24-Hour Blood
`Pressure Levels and Hemodynamic
`Responses to Physical and Mental
`Stress in Elderly Hypertensive Patients
`I. Kuwajima et al.
`962
`Loperamide Oxide in the Treatment of
`Acute Diarrhea in Adults
`A. Dettmer
`972
`Effect of Arotinolol on Insulin Sensitivity
`in Obese Hypertensive Patients
`S. Kageyama et al.
`981
`Effect of Intravenous Administration of
`EM523L on Gastric Emptying and
`Plasma Glucose Levels After a Meal in
`Patients with Diabetic Gastroparesis: A
`Pilot Study
`T. Nakamura et al.
`Membranous Glomerulonephritis in
`Patients with Rheumatoid Arthritis
`A. Yoshida et al.
`1 000
`Use of the C64 Quantitative Tuning
`Fork and the Effect of Niceritrol in
`Diabetic Neuropathy
`N. Hotta et al.
`Experimental Study on Bacterial
`Colonization of Fibrin Glue and Its
`Prevention
`K. Tanemoto and H. Fujinami
`1016
`Effect of Interferon Therapy in a Patient
`with Chronic Active Hepatitis Type C
`Associated with Interstitial Pneumonia
`and Rheumatoid Arthritis: A Case
`Report
`T. Kurihara et al.
`
`1028
`
`989
`
`1007
`
`Editorial Comment
`A. Krosnick, Editor-in-Chief
`
`911
`
`Methotrexate: The Emerging Drug of
`Choice for Serious Rheumatoid Arthritis
`R.H. Salach and J.M. Cash
`912
`
`CLINICAL STUDIES
`
`Steady-State Pharmacokinetics of
`Enteric-Coated Naproxen Tablets
`Compared with Standard Naproxen
`Tablets
`D. Jung and K.E. Schwartz
`
`923
`
`Vaginal Retention of 2% Butoconazole
`Nitrate Cream: Comparison of a
`Standard and a Sustained-Release
`Preparation
`L. Weinstein et al.
`
`930
`
`The Efficacy of Two Doses of
`Omeprazole for Short- and Long-Term
`Peptic Ulcer Treatment in the Elderly
`A. Pilotto et al.
`935
`Efficacy and Safety of Benazepril Plus
`Hydrochlorothiazide Versus Benazepril
`Alone in Hypertensive Patients
`Unresponsive to Benazepril
`Monotherapy
`K. Holwerda et al.
`Effect of lnsulin-Glipizide Combination
`on Skeletal Muscle Capillary Basement
`Membrane Width in Diabetic Patients
`R.A. Camerini-Davalos et al.
`952
`
`942
`
`PHARMACEUTICAL ECONOMICS & HEALTH POLICY
`
`Editorial Comment
`1036
`D.A. Sclar, Section Editor
`A Literature Review Comparing the
`Economic, Clinical , and Humanistic
`Attributes of Di hydroergotamine
`and Sumatriptan
`C.M. Kozma eta/.
`Cost-Effectiveness Analysis of
`Lipid-Modifying Therapy in Canada:
`Comparison of HMG-CoA Reductase
`Inhibitors in the Primary Prevention
`
`1037
`
`1052
`
`of Coronary Heart Disease
`L.L. Martens and R. Guibert
`Health Economics and Outcomes
`Research with Retrospective Data
`W.R. Simons and M.E. Smith
`1063
`Rate of Exposure to Theophylline-Drug
`Interactions
`S. Pashko et al.
`Subject Index
`
`1068
`1078
`
`DRL EXHIBIT 1018 PAGE 1
`
`

`

`Clinical Therapeutics®
`
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`
`DRL EXHIBIT 1018 PAGE 2
`
`

`

`CLINICAL THERAPEUTICS®/VOL. 16, NO. 6, 1994
`
`Steady-State Pharmacokinetics of Enteric-Coated Naproxen
`Tablets Compared with Standard Naproxen Tablets
`
`Donald Jung, PhD, and Kenneth E. Schwartz, MD
`Syntex Research, Palo Alto, California
`
`ABSTRACT
`
`In thi s open-label, randomized, cross(cid:173)
`over study, 24 healthy volunteers (12
`men and 12 women) received either en(cid:173)
`teric-coated (EC) naproxen tablets 500
`mg twi ce daily or standard naproxen
`tablets 500 mg twice daily for 7 days.
`In each of the two study periods, blood
`sampling began o n day 8, after one last
`dose of the s tudy dru g was ad mini s(cid:173)
`tered, to determine and compare steady(cid:173)
`state pharmacokinetics for each of the
`two naproxen formulations. The plasma
`half-life of naproxen averaged 16.3 and
`16. 9 hours following EC naproxen and
`standard naproxen treatments, respec(cid:173)
`tively. Mean time to maximum plasma
`concentration (T max) was g reater for EC
`naproxen than for stand ard naproxen
`(4.0 vs 1.9 ho urs), while the maximum
`observed plasma concentration (Cmax)
`was sli g htly, but not sig nifi ca ntl y,
`s mall er (94.9 vs 97.4 µ g/mL, respec(cid:173)
`tively). The mean values for average
`
`plasma concentration (Cave) and mini(cid:173)
`mum pla sma concentration for EC
`naproxen were 70.4 and 60.6 µg/mL,
`respectively, compared with 63.9 and
`44.1 µ g/mL for s tandard naproxen.
`The mean plasma fluctuation about the
`mean was g reater
`for
`standard
`naproxe n than for EC naproxen (85.3 %
`vs 49.3%), while the mean area under
`the plasma concentration-time curve
`(AUC) was s maller for standard
`naproxen (766.8 vs 845.0 µ g x h/mL).
`At steady state, EC naproxen was sim(cid:173)
`ilar to standard naproxen tablets with
`respect to Cmax, Cave, Cma,:Cave, 0- to 12-
`hour AUC, and half- life but differed in
`T max-
`In additi on, flu ctuations about
`Cave in pl as ma levels were considerably
`lower with EC naproxe n than with
`standard naproxen.
`
`INTRODUCTION
`
`Naproxen is a nonsteroidal anti-inflam(cid:173)
`matory drug with analgesic and antipy-
`
`0149-291 W4IS3.S0
`
`923
`
`DRL EXHIBIT 1018 PAGE 3
`
`

`

`retie properties. The e fficacy and tol(cid:173)
`e rability of napro xen in the ma nage(cid:173)
`me nt o f rheumatoid di sease s, go ut,
`pain, and dysmenorrhea have been well
`establi shed in ma ny years of c linical
`use. 1 An enteric-coated (EC) formula(cid:173)
`tion' of naproxen was developed to re(cid:173)
`lease na proxe n at the pH level of the
`small intestine , where di ssolution takes
`place.
`An in vi vo eva lu ati o n o f EC na(cid:173)
`proxe n tabl e ts ha s s how n th a t the
`naproxen blood levels over time were
`cons istent with th e delayed re lease of
`naproxen from the tabl ets,2 but no data
`comparin g the steady-state pharmaco(cid:173)
`kinetics of EC naproxe n with standard
`na proxe n ha ve been publi she d. The
`current study was designed to compare
`the stead y-s tate pharmacokin eti cs of
`EC naproxe n and standard tabletst in a
`group of health y men and women.
`
`SUBJECTS AND METHODS
`
`Thi s was an o pe n-labe l, rando mi zed
`stud y o f c rossover des ig n. Twe nty(cid:173)
`four heal thy men and wo men w hose
`body weights were within 15% of the
`average weig ht for th e ir age and
`height, as determined from the Metro(cid:173)
`po litan Life Insurance tables, partici(cid:173)
`pated in the study. 3 Participants we re
`selected on the basis of an essentially
`problem-free medical history, a normal
`phy s ica l e xamina tion , and a ro utine
`laboratory test profile showing no clin(cid:173)
`ically sig nificant abnormalities. Ins ti(cid:173)
`tutio nal review board approval was ob(cid:173)
`ta in ed . The study was ex pla ined to
`
`Trademarks: EC-Naprosyn®' and Naprosyn®t (Syn(cid:173)
`tex Laboratories, Inc., Palo Alto, California).
`
`924
`
`CLlN ICAL THERAPEUTICS®
`
`subjects in no ntechnical terms, and all
`subjects signed a written informed con(cid:173)
`sent form and an Experimental Subjects
`Bill of Rights before participating.
`The two study regimens were: 500-
`mg EC naproxen tablets twice daily fo r
`7 days plus one d ose o n day 8, and 500-
`mg standard naproxen tablets twice daily
`for 7 days plus one dose on day 8.
`After an overnig ht fast (beginning at
`9:30 PM the prev ious night), each sub(cid:173)
`ject received, in random order, 500 mg
`twice daily EC na proxe n or sta ndard
`naproxen for 7 days and a fin al dose on
`day 8. Adverse e vents were mo nitored
`at each blood d rawing, and the subjects
`informed the study physician or trained
`o bserver of any ad ve rse events that oc(cid:173)
`curred during the study. A washout pe(cid:173)
`riod of 8 days fo llowed each treatme nt.
`Se ri al bl ood samples we re collected
`afte r the fin al morning dose for up to
`72 ho urs. To det ermin e naprox e n
`tro ug h leve ls, s ing le blood sa mple s
`were also collecte d on days 6 and 7 be(cid:173)
`fore the morning dose. The plasma from
`each bl ood sample was separated i m(cid:173)
`medi ate ly, tra nsferred into vials, and
`frozen for subsequent assay of naprox(cid:173)
`e n by us in g hig h-performance liquid
`chromatog raphy. 4 Plas ma levels below
`the qua nti fi catio n lim it of 0.5 µ g/mL
`naproxen at time zero were set to zero
`for the calculation of mean plas ma lev(cid:173)
`els and computed variables.
`
`StaJistical and Pharmacokinetic Analyses
`
`The foll owing pharmacokinetic vari(cid:173)
`ables were determined on day 8:
`•T max-time to maxi mu m p las ma
`concentratio n;
`•Pl as ma ha lf- life- computed over
`the 24- to 72-hour interval by using log
`
`DRL EXHIBIT 1018 PAGE 4
`
`

`

`D. JUNG AND K.E. SCHWARTZ
`
`Table I. Demographic characteristics.
`
`Variable
`
`Age (y)
`Mean±SD
`Range
`Body weight (kg)
`Mean±SD
`Range
`Height (cm)
`Mean±SD
`Range
`
`Men (n = 12)
`
`Women (n = 12)
`
`29.8± 4.6
`22- 35
`
`82± II
`64-94
`
`184±6
`175- 193
`
`30.9 ±7. 1
`22-47
`
`64±6
`55- 75
`
`168±6
`157-1 76
`
`linear regression analysis of the plasma
`concentration versus time data;
`•Cmax- maxi mum observed pl as ma
`concentration;
`•0- to 12-hour AUC-area under the
`plasma concentration-time curve from
`0 to 12 hours, computed using the lin(cid:173)
`ear trapezoidal rule;
`•Cave-average plasma concentration
`computed as the ratio of AUC divided
`by the dosing interval (12 hours);
`•C1ow-minimum (troug h ) pl as ma
`concentration at time of dosing com(cid:173)
`puted as the mean of the zero and 24-
`hour values ;
`•Cma, :C1ow- peak to trough plas ma
`ratio;
`•Cma, :Cave-peak to average plasma
`concentration ratio;
`•Fluctuation-100 x (Cmax - Cmin)/
`Cave ( ie, percent fluctuation about aver(cid:173)
`age plasma concentration).
`An analysis of variance (AN OVA)
`model appropri ate for a crossover de(cid:173)
`sign was used, 5 and the statistical anal(cid:173)
`yses were performed for the pharmaco(cid:173)
`kineti c variables according to the
`General Linear Mode l procedure of the
`Statistical Analysis System, Version
`5.16. 6 The ANOVA model in c luded
`
`terms for sequence, subjects within se(cid:173)
`quence, formulation, and period effects.
`Ninety percent c lassic confidence in(cid:173)
`tervals7 for the ratio of EC naproxen to
`standard naproxen were obtained using
`the t distribution. Confidence limits
`(90%) on the difference in the regime n
`means were computed using an error
`term derived from ANOVA. These lim(cid:173)
`its were then expressed as percentages
`of the re ference mean by di viding the
`upper and lower limits of the confi(cid:173)
`dence inte rval by the estimated refer(cid:173)
`ence mean and then adding 100%. Two
`reg imens we re considered equi vale nt
`with respect to a given variable if the
`two means differed by less than 20% or
`the confidence interval was within 80%
`to 120%, with 90% confidence.
`In addition, the trough levels on days
`6, 7, and 8 were compared to demon(cid:173)
`strate that steady-state levels had bee n
`attained by day 8. ANOVA procedures
`with terms in the model for subject and
`day were used for this comparison.
`
`RESULTS
`
`The demographic characteristics (Table
`I) were calculated separately for the 12
`
`925
`
`DRL EXHIBIT 1018 PAGE 5
`
`

`

`men and 12 women in the study. All
`subjects completed the study normally.
`Adverse events were reported by 9
`(37.5%) of 24 subjects. Headaches and
`gastrointestinal complaints were the
`most frequently reported adverse events.
`With the standard naproxen tablet regi(cid:173)
`men, headaches and stomachaches oc(cid:173)
`curred in three subjects and dyspepsia
`in one. With the EC naproxen regimen,
`headaches occurred in three subjects,
`but there were no gastrointestinal com(cid:173)
`plaints. Most events associated with
`the two naproxen regimens were classi(cid:173)
`fied by the investigator as probably not
`related to the study medication , and
`none were clinically serious. Concom(cid:173)
`itant medications take n during the
`s tudy were not considered like ly to
`affect the conduct or outcome of the
`
`CLINICAL THERAPEUTICS®
`
`stud y. Laboratory tests and physical
`examinations revealed no c lini call y
`significant abnormalities.
`Stati stically s ignificant (P < 0 .05)
`diffe re nces in troug h concentrations
`between day s were observed for the
`naproxen standard tablets; there were
`no statistically significant time (day)
`effects for th e EC naprox e n table ts
`(Table II). The mean trough levels for
`the standard naproxen tablet were 46.0,
`49.9, and 45.9 µg/mL for days 6, 7, and
`8, respectively. The significant differ(cid:173)
`ence was owing to a higher naproxen
`concentration on day 7 than that o n
`da ys 6 and 8. The ratios and confi(cid:173)
`dence limits (90%) were calculated for
`the ratios of days 6 and 7 to day 8 for
`each formulation and are shown in
`Table II. Although significant day ef-
`
`Table IT. Naproxen trough plasma concentrations (µg/mL) and steady-state comparisons.
`
`p•
`
`0.244
`
`0.020
`
`Day6
`
`Day7
`
`Day8
`
`Day6:8
`
`Day7:8
`
`Ratio
`
`ECNaproxen
`Mean
`SD
`Cvar
`Minimum
`Maximum
`Ratio(%)
`cit
`Standard Naproxen
`Mean
`SD
`Cvar
`Minimum
`Maximum
`Ratio(%)
`cit
`
`73.4
`18.8
`25.7
`46.1
`120.4
`
`46.0
`9.0
`19.5
`27.8
`64.1
`
`76.8
`23.3
`30.4
`20.7
`123.1
`
`49.9
`11.9
`23.8
`26.7
`77.6
`
`68.5
`2 1.1
`30.8
`29.0
`115.2
`
`45.9
`9.4
`20.6
`26.6
`65.4
`
`107
`95-11 9
`
`11 2
`100-124
`
`100
`95-106
`
`109
`103- 114
`
`EC= enteric-<:oated; Cvar = coefficient of variation; CI= confidence interval.
`• P value is for day effect (analysis of variance model has terms for subject and day).
`t90% Cl (limits in %).
`
`926
`
`DRL EXHIBIT 1018 PAGE 6
`
`

`

`D. JUNG AND K.E. SCHWARTZ
`
`- 80
`..J 1 :::t - 60
`l!! -C
`
`40
`
`20
`
`C
`0
`:;:.
`
`~
`C
`0
`0
`
`0
`
`2
`
`4
`
`6
`
`8
`10
`Time (h)
`
`12 24
`
`48 72
`
`Figure 1. Mean naproxen plasma concentrations at steady state (day 8) over time following
`oral administration of standard naproxen <•) and enteric-coated (EC) naproxen (e ).
`fec ts were observed for the standard
`compared with 63.9 and 44.1 µ g/mL
`tablet, steady state appears to have
`for s tandard naproxen. The mean
`been reached by day 6.
`plasma fluctuation about the mean was
`The mean plasma profiles of naproxen
`greater for standard naproxen than for
`at steady state (day 8) after oral adminis(cid:173)
`EC naproxe n (85.3% vs 49.3 %), while
`tration of standard naproxen and EC
`the mean AUC was smaller (766.8 vs
`naproxen in the fasting state are plotted
`845.0 µ g x h/mL).
`in Figure 1. Figure 2 compares the two
`Table III also shows the ratios of the
`formu lations with respect to 12-hour
`various mean computed variables (EC
`AUCs for each subject.
`naproxen:standard naproxen) and the
`Table III summarizes the computed
`90% confidence intervals for the differ(cid:173)
`variab les at steady-state levels (day
`ence in means, expressed as percent(cid:173)
`8). The plasma half-life averaged
`ages. Based on the 80%: 120% rule for
`16.3 hours after EC naproxen admin(cid:173)
`bioequivalence, EC naproxen was
`istration and 16. 9 hours after standard
`bioequivalent to stan dard naproxen
`naproxen. Mean T max was greater for
`with re spect to half-life , Cmax, Cave,
`EC naproxen than standard naproxen
`Cmax:Cave, and 0- to 12-hour AUC. The
`(4.0 vs 1.9 hours), while Cmax was
`limits for the other computed pharma(cid:173)
`slightly but not significantly s maller
`cokinetic parameters (T max, C1ow, Cmax:
`(94.9 vs 97.4 µg/mL, respectively).
`C1ow, and percent fluctuation) we r e
`The mean Cave and C.ow for EC na(cid:173)
`not contained within the 80% to 120%
`proxe n were 70.4 and 60.6 µg/mL ,
`interval.
`
`927
`
`DRL EXHIBIT 1018 PAGE 7
`
`

`

`C LINICAL THERAPEUTics •
`
`1300
`
`1200
`
`1100
`
`1000
`
`-.J
`E :c
`-0
`.. ::,
`0 ::c
`N ...
`
`I
`
`X
`C)
`~ 900
`=>
`<t
`
`800
`
`700
`
`600
`
`500
`
`400
`
`0
`
`Standard Tablet
`
`EC Tablet
`
`Figure 2. Twelve-hour area under the plasma concentration-time curve (AUC) values at
`steady state (day 8) for each subject, after administration of a standard naproxen
`tablet and after an enteric-coated (EC) naproxen tablet.
`
`Table ill. Pharrnacokinetic variables (mean ± SD), ratios, and confidence intervals.
`
`Variables
`
`Half- life (h)
`Tmax (h)
`Cmax (µ g/mL)
`Cave (µ g/mL)
`C1ow (µ g/mL)
`Cmax:C1ow
`Cmax:Cave
`Fluctuation (%)
`AUC0-12 (µg x h/mL)
`
`EC Naproxen
`(A)
`
`Standard Naproxen
`(8)
`
`RatioA:8
`(%)
`
`90% CI for the
`Ratio(%)
`
`16.3 ±2.3
`4.0± 1.6
`94.9± 17.5
`70.4 ± 13.8
`60.6± 14.8
`1.6 ±0.4
`1.3 ±0. 1
`49.3 ±2 1.1
`845.0± 166.2
`
`16.9±2.3
`1.9 ± 1.2
`97.4± 12.4
`63.9 ± 9.9
`44. 1 ±9.2
`2.3 ±0.4
`1.5 ±0.2
`85.3 ± 19.3
`766.8± 118.4
`
`96. 1
`2 10.9
`97.4
`11 0.2
`137.3
`7 1.4
`88.0
`57.7
`11 0.2
`
`93.4-98.7
`181.5-240.2
`92.9-101.9
`106. 1- 114.3
`130. 1- 144.5
`66.2-76.6
`84.9-91.2
`50.3-65.2
`106. 1- 11 4.3
`
`EC= enteric-coated; CI= confidence interval; T ma,= time to maximum plasma concentration; Cma.< = maximum
`observed plasma concentration; Cave = average plasma concentration; C1ow = minimum plasma concentration;
`AUCo-12 = area under the plasma concentration-time cwve from Oto 12 hours.
`
`928
`
`DRL EXHIBIT 1018 PAGE 8
`
`

`

`D. JUNG AND K.E. SCHWARTZ
`
`DISCUSSION
`
`The EC formu lation of naproxe n dis(cid:173)
`solves at pH levels of 5.5 or greater and
`releases active drug primaril y within
`the small intestine.2 Althoug h the stan(cid:173)
`dard tablet formulation is well toler(cid:173)
`ated, it is anticipated that an EC formu(cid:173)
`lation may be preferred by some
`patients. The c urrent study was de(cid:173)
`signed to compare the stead y-s tate
`pharmacoki netics of EC naproxen and
`standard tablets in a group of healthy
`men and women.
`At s teady state , trou g h plasma
`naproxen concentrations were sig nifi(cid:173)
`cantly higher for the EC fo rmulation .
`T max was doubled for the EC prepara(cid:173)
`tion , but the max imum and average
`plasma naproxen conce ntration s and
`AUC values were si milar.
`The results of this study suggest that
`EC naproxen is most appropriate for
`the treatment of chronic pain and in(cid:173)
`flamm a tio n , rather than the initial
`treatment of acute pain. The efficacy
`of EC naproxen wo uld be similar to
`that of the standard naproxen form ula(cid:173)
`tion based on a sim ilar s teady- state
`bioavailability between the two formu (cid:173)
`lations. The most common side effects
`were h eadache a nd gastrointes tin al
`complaints.
`
`CONCLUSION
`
`In the current steady-state study, EC
`naprox en was s imilar to standard
`naproxen tablets with respect to Cmax,
`Cave, Cm.,:Cavc, 0- to 12-hour AUC, and
`half-life, but differed in T max, In addi(cid:173)
`tion, the fluctuation in plas ma levels
`
`about Cave was smaller with EC
`naproxen than with standard naproxen.
`
`Address correspondence to: Donald
`Jung , PhD, Syntex Researc h , 340 l
`Hillview Avenue, P.O. Box 10850, Palo
`Alto, CA 94303.
`
`REFERENCES
`
`I . Todd PA, C lissold SP. Naproxen-a reap(cid:173)
`praisal of its pharmacology and therapeutic
`use in rheumatoid diseases and pain states.
`Drugs. 1990;40:9 1- 137.
`
`2. Wilding IR, Hardy JG, Sparrow RA, et al. In
`vivo evaluation of enteric-coated naproxen
`tablets using gamma scintigraphy. Phann
`Res. 1992;9: 1436-1441.
`
`3. Statistical Bulletin. New York: Metropolitan
`Life Foundation; 1983;64( 1): 1-9.
`
`4. Syntex Research, Department of Analytical
`and Metabolic C hemistry. Detennination of
`Naproxen in Human Plasma by High Per(cid:173)
`fonnance Liquid Chromatography. AMC
`Method Report #040, unpublished . Palo
`Alto, Calif: Syntex, 1982.
`
`5. Winer BJ. Statistical Principles in Experi(cid:173)
`mental Design. New York: McGraw-Hill;
`1971.
`
`6. Barr AJ, Goodnight JH, Sall JP, et al. SAS
`Users' Guide. Raleigh, NC: SAS Institute,
`Inc; 1979.
`
`7. Schuirman DJ. A comparison of the two
`one-sided tests procedure and the power ap(cid:173)
`proach for assessing the equivalence of
`average bioavailability. J Pharmacokinet
`Biopharm. I 987; 15 :657--080.
`
`929
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`DRL EXHIBIT 1018 PAGE 9
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