`
`J Clin Gastmenteml' 1997;24(2):65—70.
`
`O [997 Lippincott—Raven Publishers. Philadelphia
`
`The EffeCts of Oral Doses of Lansoprazole and
`Omeprazole on Gastric pH
`
`Keith G. Tolman, M.D., Steven W. Sanders, Pharm.D., Kenneth N. Buchi, M.D.,
`Michael D. Karol, Ph.D., Dennis E. Jennings, Ph.D., and
`Gary L. Ringharn, Ph.D.
`
`.n-t-t-t-‘H—I—I-t-It-t-F
`
`We compared gastric pH values arter therapeutic doses of Ian-
`soprazole and omeptazole in 17 healthy adult men. The phar-
`macokinetics of the two drugs were studied. A three-way
`crossover design compared the effects on gastric pH of IS and
`30 mg lanscprazole and 20 mg omeprazole—each given once
`daily for 5 days. Ambulatory 24-h intragasrric pH levels were
`measured before dosing, alter the first and fifth doses in each
`period, and 15 days afier each dosing period. A positive rela-
`tionship between the lansoprazole or omeprazole area under the
`curve (AUCs) and the 24-h mean pH values was found for each
`regimen. No difi‘erences in maximum concentration (CW) and
`AUC were noted from day l to day 5 for the two lansoprazole
`doses. With omeprazole, both Cm, and AUC levels were greater
`on day 5 than on day 1. All three regimens increased 24-h mean
`gastric pH, although 30 mg lansoprazole had the most signifi-
`cant effect. The percentage of time that gastric pH was >3, >4,
`and >5 was also significantly higher with 30 mg lansoprazole.
`All three regimens were associated with reversible elevations of
`serum gastrin, which more than doubled at some points. No
`clinically significant adverse events were documented.
`Key Words: Proton pump inhibitors—Lamoprazole—Omepra—
`zole—Pharmacokinetics—Pharmacodynamics—Gastric pH—
`Serum gastrin.
`
`Despite changing concepts about the etiology of
`peptic ulcer disease, gastric acid remains the primary
`mediator of injury, and inhibition of its secretion leads
`to ulcer healing. The most effective agents in inhibit-
`ing acid secretion are the H+/K+-ATPase, or proton
`pump, inhibitors, such as omeprazole and lansopra-
`zole. Both drugs have shown considerable efficacy in
`the treatment of duodenal and gastric ulcers as well as
`
`
`Received September 22, 1995. Sent for revision November 7, 1995.
`Accepted November 7, 1996.
`From the University of Utah School of Medicine (K.G.T., S.W.S.,
`KN.B.), Salt Lake City, Utah; and Abbott Laboratories (M.D.K.. D.E.J.,
`G.L.R.), Abbott Park, Illinois, U.S.A.
`Addrem correspondence and reprint requests to Dr. Keith G. Tolman,
`Division of Gash-oenterology, University of Utah School of Medicine,
`411118 School of Medicine. 50 No. Medical Drive, Salt Lake City, UT,
`U.S.A.
`,
`
`gastro-esophageal reflux disease (GERD), and both
`are generally considered safe. Because of its effects on
`hepatic oxidative metabolism, however, omeprazole
`interacts with numerous other drugs and has the po-
`temial for toxicity based on these interactions. For ex-
`ample, omeprazole inhibits the hepatic metabolism of
`diazepam (1—3), carbamazepine (4), antipyrine and
`arninopyrine (5), and the R (but not the S) isomer of
`warfarin (6). Lansoprazcle has shown no effect on the
`metabolism of diazepam (7), phenytoin (8), antipyrine
`(8), propranolol (9), the R or S isomers of warfarin
`(10—11), or low-dose oral contraceptives (12). Theo-
`phylline clearance is marginally increased with both
`drugs (13714). Bioavailability of the two drugs after
`oral dosing also appears
`to differ:
`lansoprazolc
`bioavailability after oral dosing (15) is ~85% com-
`pared with 30—40% for omeprazole (16—17). This
`study was designed to compare the pharmacodynamic
`effects of lansoprazole and omeprazole and to deter-
`mine whether a correlation exists between plasma
`AUC values and 24-h gastric pH.
`
`MATERIALS AND METHODS
`
`Seventeen healthy adult men were enrolled in the study.
`Three left the study prematurely—one because of an abnormal
`laboratory test before drug administration and two for personal
`reasons alter 5 days of dosing. The subjects were nonsmokers
`with a mean age of 27 years (range, 1940 years), a mean height
`of 71 inches (range, 66—76 inches), and a mean weight of 173.4
`lb (range, 141—224 lb). Physical examinations, E035, and lab-
`oratory evaluations were normal at the time of entry. None of
`the subjects had a history of drug or alcohol abuse, and none
`was taking medications that might interfere with evaluation of
`the study drugs. The study was approved by the Investigational
`Review Board of the University of Utah, and all subjects gave
`written informed consent before participation.
`This was a randomized, double-blind, three-way crossover
`study comparing once-daily doses of IS and 30 mg lansopm-
`zole and 20 mg omeprazole. The selected doses were those ap-
`
`CONFIDENTIAL
`
`65
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`_j_
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`__...,:..,»,r,
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`66
`
`K. G. TOLMAN ETAL.
`
`proved. by the US. Food and Drug Administration. Each treat-
`ment period lasted 5 days, with a 2~week washout period be
`tween treatments. Postdosing evaluations were conducted
`l4»—16 days after the last dose of each treatment (hereaiter re
`ferred to as l5 dayspost-treatment).
`'
`Subjects were confined to the Drug Research Center at the
`University of Utah during the dosing periods, from the time be-
`fore dinner on day -3 to the morning of day 6, so that 24-h am-
`bulatory pH recordings could be made under controlled condi-
`tions. Standardized meals were given at 9:00 a.m., 1:00 pan,
`and 6:00 p.m. and a snack at 9:00 p.m.. Xantldnercontaining
`foods and beverages were prohibited. Study medications were
`taken at ~8:00 am. (1 h before breakfast).
`Safety evaluation included monitoring of adverse events; vi-
`tal signs, clinical laboratory results (including gastn'n levels),
`physical condition, and ECGs. On each day of confinement,
`subjects were questioned about symptoms or side‘eEects possi-
`bly related to treatment. Vital signs were recorded daily during
`confinement and again at postdosing; laboratory evaluations
`were done on days I and 6. and postdosing, interim physical ex-
`aminations were performed on days -2 and 5, and‘rECGs were
`recorded on day 5 and postdosing. Sertun gastrin- levels were
`measured from samples collected 1 h before and 1 h after meals
`on days -2, 1, and 5', 15 days post—treatment: and at the end of
`each 24-h gastric pH recording period (days -1, 2, and 6 and 15
`days post-treatment). Gash-in was measured using a'double an-
`tibody technique (Product KGAD~2, Gastrin Double Antibody;
`Diagnostic Products Corporation, Los Angelcs, CA, U.S.A.).
`
`Pharmacodynamic Evaluation
`During each crossover period, ambulatory 24»h gastric pH
`was monitored on days ~2, l, and S and on day 15 post-treat—
`ment. A monocrystallinc antimony electrode (Synectics Med--
`ical Inc., Irving, TX} was positioned in the stomach before the
`start of pH recording. Electrode placement in the stomach was
`confirmed by a drop in pH during introduction of the electrode.
`.The electrodes were connected to a Digitrapper Mark 11 single-
`channel recorder (Synectics Medical Inc.), which was cali-
`.- brated before each use with buffer solutions at pH 1 and 7. On
`‘ days 1 and 5 of each crossover period, monitoring began imme—
`diately afier drug administration and continued every 4 s for 24 .
`h. Values were digitized and stored by the Digitrapper unit. The
`median of each 15-min period was calculated for analysis.
`
`.\
`‘
`Pharmacokinetic Evaluation
`On days 1 and 5 of each treatment period, blood samples
`were drawn at several time intervals: immediately before dosing
`and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h after dosing. Venous
`plasma samples were analyzed for lansoprazole and omepruzole
`using validated high-perfonnance liquid chromatography meth-
`ods (18). The following model-independent pharmacolcinctic
`parameters were evaluated: individual plasma concentrations,
`peak concentration (Crux). time to peak concentration (Tm),
`and area under the plasma concentration curve (AUCM). Elim-
`ination half-life (ti/2) was estimated based on linear regression
`of a log-transfonncd concentration of the terminal phase of the
`individual plasma concentrations. Comparisons were not made
`between lansoprazole and omeprazole because clinical rather
`than identical doses were given.
`
`Statistical Analysis
`
`Gastric pH
`All statistical tests were two-tailed, with significance desig-
`nated as p S 0.05. The preregimen value was the value obtained
`
`JCl'r'rr Gastmenleml, Vol. 24, No. 2, [997
`
`-————-——fl——Im—
`
`I?“
`
`before each treatment regimen (day -Z); the postregimen value
`was that obtained 14—L6 days afier completion (day 15 post-
`treatrnent). The 15-min median pH values for each- subject were
`used for comparison between treatment groups. Gastric pH
`variables analyzed were mean gastric pH values (calculated as
`the average of the 15-min medians) and the percentage of time
`that gastric pH was >2, >3, >4, and >5 (based on the 15-min
`medians). All gastric pH analyses were performed over the total
`24-h period as well as over four specified time intervals
`(0800—1300, 1300—1800; 1800—2300, and 2300-0800 h). The
`onset ofaction was examined similarly on an hourly basis, with
`time to eliect described as the first. hour in which significant
`differences from baseline were noted.
`For each evaluation day, the effects of the three regimens on
`gastric pH variablestwere compared with a crossover model that
`included regimen, period, sequence, and subjects within se—
`quence as. factors. Within each regimen, gastric pH variables
`were compared across days using a repeated—measures model
`that included day, sequence, and subject as factors. Within the
`framework of this model. pairwise comparisons were made of
`day] versus preregi'men, day 5 versus preregimen, day 5 versus
`day 1, and day 15 post-treatment versus preregimen.
`Pharmacokz‘neritcs
`Analyses of variance were performed for lansoprazole and
`omeprazole pharmacokinetic parameters. For lansopra'zole, the
`following effects were included in the model: period, subject,
`dose, day, pcriod-by—day interaction, and dose—by-day interac-
`tion. For omeprazoie, the effects included were period. subject
`nested within period. and day. The C...“ and AUC values from
`the 30-mg lansoprazole regimen were normalized to a lS-mg
`dose to judge dose proportionality.
`\,
`
`Relationship- ofAUC to Gastric pH
`Analysis ofoovariance was employed to explore the relation-
`ship between 24-h average gastric pH and plasma AUC for lan-
`soprazole and:omeprazol'e;.The dependent variable was average
`pH; the covariatewas the natural logarithm of AUC. For lanso-
`prazole, an analysis was performed for data on days 1 and 5
`jointly. with: effects for period, day, subject. day-by-subject in—
`teraction, and separate slopes (interaction between day and
`AUC) in the initial model. The relationship between the 24-h
`average gastric pH and the plasma drug concentration AUC was
`also examined‘using a sigmoidal E...“ model (19—21).
`Serum Gastrin
`Gastrin values were measured 1 h before and after each meal
`on day -2 (preregimen), days 1 and 5, and day 15 (post-treat»
`merit) for each of the three regimens. An additional measure-
`ment was obtained 14 h after dinner. Gash-in variables analyzed
`included values at each ofthcsc time points as well as integrated
`gastrin, definedas the area under the gastrin curve from 1 b be—
`fore breakfast to 1 h after dinner (0800—1900), as calculated by
`the trapezoidal method. Changes from preregimen scrum gas-
`trin values were. analyzed between and within regimens using
`the crossover andirepeated-measures model, respectively.
`
`Safest
`The incidence of adverse events during each regimen, or
`within 3 days of the last dose of any regimen, were tabulated
`and grouped by the COSTART term and body system. Changes
`from prercgimen clinical
`laboratory variables and vital signs
`were compared using the crossover model‘described for gastric
`pH; changes in ECG and results of physical examination were
`reviewed and tabulated.
`
`
`
`CONFIDENTIAL
`
`PZOO103625
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`Patent Owners' Ex. 2034
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`lPR2018-00272
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`

`RESULTS
`
`Gastric pH
`Gastric pH. as shown in Fig. 1, increased signifi-
`cantly on all three regimens, but was highest on the 30-
`mg lansoprazole regimen. The difference between the
`30-mg dose of lansoprazole and either 20 mg omepra-
`zole or 15 mg lansoprazole was statistically significant
`afier the first and fifth doses (p 5 0.002). At almost all
`time points, gastric pH was significantly higher with
`the 30-mg dose of lansoprazole than with the other two
`regimens (p < 0.05). No statistically significant differ-
`ences were evident between 15 mg lansoprazoie and
`20 mg omeprazole.
`Figure 2 shows the mean gastric pH over 24 h for all
`' three regimens, including a combined preregimen pro-
`file (an average of the three preregimen values). Gas-
`tric pH was consistently higher with 30 mg lansopra-
`zole than with the other two regimens. Gastric pH
`remained above 3, 4, and 5 longest in the 30-mg lan-
`soprazole regimen after both the first and fifth dose. A
`statistically significant difference (p <0.01) in the
`mean percentage of time pH was >3, >4, and >5 on
`day 5 was observed between 30 mg lansoprazole and
`the other two regimens (Fig. 3). Gastric pH rose more
`rapidly after 30 mg lansoprazoie than after the other
`two regimens.
`Pharmacokinetics
`
`Details of the pharmacokinetic parameters for all
`three regimens are shown in Table 1. There were no
`statistically significant differences between day l and
`day 5 in Cmax, Tmax, tlfz, or AUC (Fig. 4A) for the two
`lansoprazole doses, nor was there a statistically signif-
`icant difference in dose-normalized Cmax and AUC for
`
`
`
`—.-— Larisopraaoia 30 mg
`—I— Lansoprarole 15 mg
`"'0'" Omeprazoie 20 mg
`
` GastricpH
`
`
`Pro-Regimen
`Day 1
`Day 5
`15 Days Post
`FIG. 1. Mean 24-h gastric pH levels. The asterisks mark
`statistically significant difierences (p 5 0.002) between 30
`mg lansoprazole and 20 mg omeprazole or 15 mg Ianso-
`prazole.
`
`CONFIDENTIAL
`
`.
`
`"L“‘J‘Z 77... $7., 7..
`
`
`
`”(##IJ'IUI‘JW
`GastricpH
`
`1200
`
`1600
`
`800
`nose TIME
`
`2000
`“me
`
`2400
`
`400
`
`300
`
`Mean
`
`
`
`MeanGastricpH
`
`a. Day 5
`
`.......... Confined Pro-Hm
`__ leeprlzolo 15 mg
`
`unsound. 313 mu
`........... Omprlmle 20 mg
`A TIMI ol Meals
`
`
`
`(r.
`if
`
`L'
`
` 800 1200 1600 2000 2400 400 300
`
`DOSETII'IE
`Time
`
`
`
`
`
`
`
`
`
`
`
`FIG. 2. Mean gastric pH for the two iansoprazole and the
`omeprazoie regimens on day 1 (A) and day 5 (B).
`
`the two regimens. For omeprazolc, no statistically sig-
`nificant differences in Tm or tn: between day I and
`day 5 were observed. Differences did exist between
`day l and day 5 results of other pharmacokinetic para~
`meters, including Cm, AUC (Fig. 4B), dose-normal-
`ized Cm“, and dose-normalized AUC, all of which
`were higher on day 5 than on day 1 (p < 0.05). For both
`lansoprazole and omeprazole, a significant positive re-
`lationship was found between 24-h pH and AUC val-
`ues, that is, increased gastric pH correlated with in—
`creased AUC values. Figure 5 shows a comparison of
`the mean day 5 24-11 pH plotted against AUC and in-
`cludes the regression curves obtained from the sig—
`moid Em model.
`
`Serum Gash-in
`
`Increases in serum gastrin levels from preregimen
`to day 5 were significant with all three regimens (p <
`0.05). In most instances, day 5 values were signifi-
`cantly higher than the corresponding day 1 values and
`were similar for all regimens (Table 2). Two weeks af-
`ter dosing, serum gastrin tended to return to preregi-
`
`J Clin Gastmenremi, Vol. 24. Na. 2, N97
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`
`
`68
`
`K. G. IOLMAN ETAL.
`
`TABLE 1. Pharmacokinetic parameters for iansoprazoie and omeprazoie (mean :i: SD} .
`Cm dose. normalized
`AUC dose, normalized
`
`([ng/lemg)
`Tm (h)
`1'. (h)
`Cmu (nglml) AUG (ng-h/ml)
`([ng-h/millmg}
`
`Lansoprazcle. 15 mg
`Day 1
`Day 5
`Lansoprazola. 30 mg
`1,371 a 755
`Day 1
`298 c1861
`Day 5
`‘
`Omeprazole, 20 mg
`14.90 :t: 9.30
`10.85 a: 7.00
`298 a 186
`217 t 140
`0.62 a: 0.32
`1.7 $1.3
`Day 1
`29.75 1: 18.85‘
`15.75 1 7.45if
`595 1: 3773
`315 a: 149'3
`0.37 a; 0.50
`1.6 :1: 0.7
`Day 5
`—mm___.—__—]_
`
`1.6 a: 0.7
`1.5 a: 0.5
`
`1.5 a 0.3
`1.7 :1.3
`
`1.06 :1: 0.43
`1.09 a: 0.56
`
`335 :199
`351 21.31
`
`623 1 237
`723 i 323
`
`0.97 2 0.33
`0.62 :t 0.32
`
`729 t 385
`217 2140
`
`22.33 113.27
`23.40 :1: 8.73
`
`24.30 a 12.83
`10.85 1 7.00
`
`41.53 t 19.13
`48.20 2 2i.53
`
`45.70 x 25.17
`14.90 1 9.30
`
`It
`If:
`
`it
`
`-:
`' _
`
`ll
`
`l-
`
`"t_i"i
`
`1
`
`l
`i
`
`aStatistically significantiy higher than day t (p < 0.05).
`
`men levels; there were no statistically significant dif-
`ferences between the preregimen and postregirnen gas-
`trin levels in any treatment regimen.
`Adverse Events
`
`Adverse events were reported by five subjects (31%]
`on the lS-rng lansoprazole regimen, six (43%) on the
`30-mg1ansoprazole regimen, and six (40%) on the 20—
`mg omeprazole regimen. Events that were reported by
`two or more subjects in any treatment group included
`asthenia, headache, dizziness, and acne (two subjects
`reporting each event) on the lS—mg lansoprazole regi-
`men; headache (six subjects) in the 30-mg lansoprazole
`regimen; and nausea and acne (two subjects each) on
`the 20-mg omeprazole regimen. There were no clini-
`cally significant changes in physical examinations,
`ECGs, vital signs, or laboratory tests of hematology,
`chemistry, or urinalysis in any treatment regimen. One
`subject with a normal screening alanine aminon‘ans-
`ferase (ALT) level (27 IU/L) had elevated values (81
`MIL) just before dosing with 15 mg lansoprazole; on
`day 4 of the first crossover period, his ALT had in-
`creased to 224 IU/L, and bows discontinued from the
`
`80%
`
`a Lansoprazole t5 mg
`I unsoprazole 30 mg
`El Omeprazgle 20 mg
`
`
`
`'16Time(24h)atSpecifiedpH
`
`60%
`
`40%
`
`20%
`
`0%
`
`FIG. 3. Mean percentage of time gastric pH was >3, >4,
`and >5 on day 5. The asterisks mark statistically signifi-
`cant differences (p s 0.01) between 30 mg Iansoprazole
`and the other two regimens.
`
`J C101 Gmrmenteml. Fat. 24. N0. 2. 1997
`
`CONFIDENTIAL
`
`study after testing positive for hepatitis C. Another sub-
`ject had elevated AST/ALT values attributed to study
`drugs at the end of each crossover period. His pretreat-
`ment AST and ALT levels were 30 and 36 l'U/L, re-
`spectively. After the fifth dose of 30 mg iansoprazole,
`values were 57 and 108 IU/L, respectively; by the post-
`treatment examination, AST/ALT values had decreased
`to 30 and 45 IUIL, respectively.
`
`1000
`900
`800
`700
`600
`
`o§§§§§
`
`1000
`900
`800
`700
`600
`500
`400
`300
`200
`100
`
`
`
`Lansoprazole(ngImL)
`
`
`
`Omeprazole(nglmL)
`
`A. Lansoprazole
`
`
`Lansoprazoie 15 mg. Day 1
`Lansoprazole 15 mg. Day 5
`Lansoprazole 30 mg. Day 1
`Lansoprazole 30 mg. Day 5
`
`
`
`
`+¢Ii4]
`
`- Hours
`
`B. Omeprmle
`
`-A- OmpmzoleZO mg. Day1
`+ Omeplazole 20 I119. Day 5
`
`
`
`Hours
`
`FIG. 4. Mean plasma concentrations of lansoprazole (A)
`and omeprazole (B) on days 1 (A) and 5 (B).
`
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`
`EFFECT OF LANSOPRAZOLE AND OMEPRAZOLE 0N GASTRIC PH
`
`69
`
`of the H+/K+-ATPase, it is likely that the higher gas-
`tn'c pH produced by repeated dosing represents an ac-
`cumulation of blocked enzyme and fewer functional
`proton pumps (27,28).
`Meta-analyses of several clinical studies found a
`significant correlation between the degree of acid sup-
`pression and the rate of healing in both ulcer disease
`and reflux esophagitis (29—30). For duodenal ulcer, a
`significant correlation existed for healing and degree
`and duration of gastric acid suppression. The healing
`rate increased as gastric pH and duration of acid sup-
`pression increased. The model demonstrated the im-
`portance of raising gastric pH to 3 and indicated that
`further elevation had a negligible effect. Both the du-
`ration of time (hours per day) that gastric pH was 23
`and the duration of therapy (weeks) were more impor-
`tant than further elevation of pH. In gastric ulcer, a
`correlation also existed between suppression of 24-h
`gastric acidity and healing rates after 2, 4, and 8 weeks
`of treatment, although the correlation was less marked
`than for duodenal ulcer. In reflux esophagitis, Bell et
`a1. (31) reported that maintaining pH levels above 4
`was the most important factor in predicting healing
`rate. In this study, the mean time pH levels were above
`3 and 4 was significantly greater with 30 mg lanso—
`prazole than 20 mg omeprazole or 15 mg lansopra-
`zole. It is uncertain whether this translates to more
`complete healing, although it may translate to more
`rapid healing.
`The healing rate for duodenal ulcer is already close
`to 100%“, but the healing rates for gastric ulcer and
`GERD could be improved. Healing rates for GERD,
`particularly resistant esophagitis, are improved with
`proton pump inhibitors, as suggested by studies indi-
`eating a relationship between healing and degree of
`acid suppression (3 1,32). Healing of esophageal ulcer-
`ation correlates with an increase in gastric pH rather
`than with prevention of reflux per se. In this regard,
`both omeprazole and lansoprazole have showneffi-
`cacy in the treatment of GERD (3244). The dose—re—
`lated suppression of gastric acid observed in our study
`parallels the dose-related healing of GERD (31).
`As expected, both lansoprazole and omeprazole
`caused reversible increases in serum gastrin leveis.
`Serum gastrin increased more with the ISO-mg dose of
`lansoprazole, in agreement with the well-known rela-
`tionship between the extent of acid inhibition and the
`extent of increase in fasting gastrin concentrations
`(25). However, no subject in the study experienced an
`increase in gastrin values more than double the upper
`limit of normal, and all values returned to the normal
`range within 15 days of discontinuing medication. The
`magnitude of changes and their return to preregimen
`levels are similar to findings of other published stud-
`
`J Clin Gastmem‘eml. Pb}. 24. No. 2. {997'
`
`B 7 6
`
`E_ 5
`:r
`
`a?
`v 4N
`
`5 3
`g
`
`
`
`.
`
`o Lansoprazole, Days
`
`O Omeprazoie. Day 5
`— Lansoprazola Slgmold Emax, Day 5
`
`----- Omeprazcla Sigmold Emax. Day 5
`
`0
`500
`1WD
`1500
`2000
`2500
`3000
`3500
`AUG
`
`FIG. 5. Day 5 mean 24-h pH versus AUC sigmoid Ema;
`model.
`
`DISCUSSION
`
`Pharmacokinetic parameters in our study are similar
`to data obtained from other studies for both lansopra—
`zole and omeprazole (22—24). Dose-normalized CW
`and AUC values were not different for the two doses of
`lansoprazole. With omeprazole, CW and AUC levels
`were significantly higher on day 5 than on day 1', an ef-
`fect also described by Clissold and CampoIi-Richards
`(24), suggesting that omeprazole’s bioavailability in-
`creases with repeated administration. Because the
`study was designed as a pharmacodynamic study, and
`because we did not use equal doses of omeprazole and
`lansoprazole, we did not make a direct statistical com—
`parison of the pharmacokinetic profiles of these two
`drugs; rather, our aim was to compare their effects on
`gastric pH and to determine whether a relationship ex-
`ists between plasma AUC and mean 24-h gastric pH.
`A positive relationship was found between AUC and
`mean 24-h gastric pH for both lansoprazole and
`omeprazole—an observation in keeping with those of
`earlier studies (25,26). Both drugs produced signifi-
`cant increases in gastric pH, although 30 mg lansopra—
`zole was more potent that either 15 mg lansoprazole or
`20 mg omeprazole, which were comparable to each
`other. Since both drugs produce irreversible inhibition
`
`TABLE 2. Mean fasting serum gastrin levels (pg/ml)a
`15 mg
`30 mg
`20 mg
`Lansopmzola
`Lansoprazole
`Lansopr‘azole
`
`Time point
`
`33.1
`41 .2"
`33.7
`Preregirnen
`42.?
`45.3
`40.3
`Day 1
`59.2 .
`59.3
`52.9
`Day 5
`
`
`37.715 Days after regimen 34.6 32.1
`
`'1 h beIore bedtime.
`”Significanlly higher the 15 mg Iansoprezole and 20 mg omeprazole [p
`s 0.05).
`
`CONFIDENTIAL
`
`PZOO103628
`
`WV|M0184258
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`Patent Owners' Ex. 2034
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`lPR2018-00272
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`Page 5 of 6
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`Patent Owners' Ex. 2034
`IPR2018-00272
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`

`

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`K. G. TOLMAN ETAL.
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`poptic ulcer disease and GERD,
`the results of our
`Study
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`treatment for duodenal ulcer, gastric ulcer, and GERD.
`
`Acknowledgment: This study was supported by a grant from
`TAP “unneceuficals- Waffle“: 1“"“115-
`
`_
`
`'=
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`JClin Gartmnlerni. VOL 24, Na, 2, [997
`
`CONFIDENTIAL
`
`PZOO103629
`
`WV|M0184259
`
`Patent Owners' Ex. 2034
`
`lPR2018-00272
`
`Page 6 of 6
`
`Patent Owners' Ex. 2034
`IPR2018-00272
`Page 6 of 6
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`