tageHenkeaeeeeic
`
`
`J Clin Gastroenterol 1997;24(2):65-70.
`
`© 1997 Lippincow-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.p.,
`Michael D. Karol, ph.p., Dennis E. Jennings, Ph.D., and
`Gary L. Ringham,Ph.D.
`
`We compared gustric pH values after therapeutic doses of lan-
`soprazole and omeprazole 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 15 and
`30 mg lansoprazole and 20 mg omeprazole—eachgiven once
`daily for 5 days, Ambulatory 24-h intragastric pH levels were
`measured before dosing, after the first and fifth doses in each
`period, and 15 days after each dosing period. A positive rela-
`tionship between the lansoprazole or omeprazole area underthe
`curve (AUCs) and the 24-h mean pH values was found for each
`regimen. No differences in maximum concentration (Cmax) and
`AUC were noted from day 1 to day 5 for the two lansoprazole
`doses. With omeprazole, both Crox 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-
`canteffect. The percentage oftime that gastric pH was >3, >4,
`and >5 wasalso 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—Lansoprazole—Omepra-
`zole—Pharmacokinetics—Pharmacodynamics—-Gastric pH—
`Serum pastrin.
`
`Despite changing concepts about the etiology of
`peptic ulcer disease, gastrie acid remains the primary
`mediatorofinjury, and inhibition ofits 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
`eee
`
`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., 5,WS.,
`K.N.B.), Salt Lake City, Utah; and Abbott Laboratories (M.D.K., BEL,
`G.L.R.), Abbott Park,Illinois, U.S.A.
`Address correspondence and reprint requests to Dr. Keith G. Tolman,
`Division of Gastroenterology, University of Utah School of Medicine,
`4R118 Schoo! of Medicine, 50 No. Medical Drive, Salt Lake City, UT,
`US.A,
`.
`
`gastro-esophageal reflux disease (GERD), and both
`are generally considered safe. Becauseofits effects on
`hepatic oxidative metabolism, however, omeprazole
`interacts with numerous other drugs and has the po-
`tential for toxicity based on these interactions. For ex-
`ample, omeprazole inhibits the hepatic metabolism of
`diazepam (1-3), carbamazepine (4), antipyrine and
`aminopyrine (3), and the R (but not the S) isomer of
`warfarin (6). Lansoprazole 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 (13-14). Bioavailability of the two drugs after
`aral dosing also appears
`to differ:
`lansoprazole
`bioavailability after oral dosing (15) is ~85% eom-
`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 after 5 days of dosing. The subjects were nonsmokers
`with a mean age of 27 years (range, 19-40 years), a mean height
`of 71 inches (range, 66-76 inches), and a mean weight of 173.4
`lo (range, 141-224 Ib), Physical examinations, ECGs, 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 mightinterfere 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 dases of 15 and 30 mg lansopra-
`zole and 20 mg omeprazole. The selected doses were those ap-
`
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`
`CONFIDENTIAL
`
`Page 1 of 6
`
`65
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`soap sneHiHEROESeHll gE Ge cai
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`is Bilis:
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`
`66
`
`&.G. TOLMANETAL.
`
`proved. by the U.S, Food and Drug Administration, Each treat-
`ment period lasted 5 days, with a 2-week washout period be-
`tween treatments. Postdosing evaluations were conducted
`14-16 days after the last dose of each treatment (hereafter re-
`ferred to as 15 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-br am-
`bulatory pH recordings could be made under controlled condi-
`tions. Standardized meals weregiven at 9:00 a.m., 1:00 pum.,
`and 6:00 p.m. and a snack at 9:00 p.m.. Xanthine-containing:
`foods and beverages were prohibited. Study medications. were
`taken at ~8:00 a.m.(1 h before breakfast}.
`Safety evaluation included monitoring of adverse events, vi-
`tal signs, clinical laboratory results {including gastrin levels),
`physical condition, and ECGs. On each day of confinement,
`subjects were questioned about symptoms or side'effects possi-
`bly related to treatment. Vital signs were recordeddaily during
`confinement and again at postdosing; laboratory cvaluations
`were done on days | and 6, and postdosing, interimphysical ex-
`aminations were performed on days -2 and 5, and‘ ECGs were
`recorded on day 5 and postdosing. Serum gastrinlevels 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 ond of
`each 24-h gastric pH recording period (days ~1, 2, and 6 and 15
`days post-treatment). Gastrin was measured using adouble an-
`tibody technique (Product KGAD-2, Gastrin Double Antibody;:
`Diagnostic Products Corporation, Los Angeles, CA, ULS.A.).
`
`*
`
`Pharmacodynamic Evaluation
`During each crossover period, ambulatory 24-h gastric pH
`was monitored on days -2, 1, and 5 and on day 15 post-treat—
`ment. A monocrystalline antimony ¢lectrode (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 duringintroduction ofthe electrode.
`The electrodes were connected to a Digitrapper MarkII single-
`channel recorder (Synectics Medical Inc.), which was cali-
`- brated before each use with buffer solutions at pH | and 7, On
`“days 1 and 5 of cach crossover period, monitoring began imme-
`diately after drug administration and continued every 4s 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 $ 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 omeprazole
`using validated high-performanceliquid chromatography meth-
`ods (18). The following model-independent pharmacokinetic
`parameters were evaluated: individual plasma concentrations,
`peak concentration (Cmax), time to peak concentration (Tmax),
`and area under the plasma concentration curve (AUC,_.). Elim-
`ination half-life (ti2) was estimated based onlinear regression
`of a log-transformed 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 $0.05. The preregimen value was the value obtained
`
`J Clin Gastroenteral, Vol. 24, No. 2, 7997
`
`before each treatment regimen (day -2); the postregimen value
`was that obtained 14-16 days after completion (day 15 post-
`treatment), 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 [5-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 overthe 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 effect 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 variables: were 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
`day1 versus preregimen, day 5 versus preregimen, day 5 versus
`day 1, and day 15 post-treatment versus preregimen.
`Pharmacokinetics
`Analyses of variance were performed for lansoprazole and
`omeprazole pharmacokinetic parameters. For lansoprazole, the
`following effects were included in the model: period, subject,
`dosc, day, period-by-day interaction, and dose-by-day interac-
`tion. For omeprazole, the effects included were period, subject
`nested within period, and day. The Crax and AUC values from
`the 30-mg lansoprazole regimen were normalized to a 15-mg
`dose to judge dose proportionality.
`\
`
`Relationship-ofAUC to Gastric pH
`Analysis of covariance was employed to explore the relation-
`ship between 24-h average gastric pH and plasma AUC for lan-
`soprazole and:omeprazole:.The dependent variable was average
`pH;the covariate. was the natural logarithm of AUC. For lanso-
`prazole, an analysis was performed for data on days 1 and 5
`jointly, witheffects 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 andthe plasma drug concentration AUC was
`also examinedusing a sigmoidal Emax modet (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-
`ment) for each of the three regimens. An additional measure-
`ment was obtained 14 h after dinner. Gastrin variables analyzed
`included values at each of these time points as well as integrated
`gastrin, defined.as the area under the gastrin curve from 1 h be-
`fore breakfast to 1 h after dinner (0800-1900), as calculated by
`the trapezoidal method, Changes from preregimen serum gas-
`trin values were. analyzed between and within regimens using
`the crossover and'repeated-measures model, respectively.
`
`Safety
`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 COSTARTterm and body system. Changes
`from preregimen. clinical
`laboratory variables and vital signs
`were compared using the crossover model described for gastric
`pH; changes in ECG andresults of physical examination were
`reviewed and tabulated.
`
`
`
`CONFIDENTIAL
`
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`sissonsangeet
`
`
`
`EFFECT OF LANSOPRAZOLE AND OMEPRAZOLE ON GASTRIC PH
`
`67
`
`RESULTS
`
`Mean
`
`DOSE TIME
`
`2000
`Time
`
`2400
`
`400
`
`800
`
`B. Day 5
`
`GastricpHme&>aoa~~oO 800=1200«=1600S
`
`
`
` MeanGastricpH
`
`ee
`
`ff
`
`
`
`Gastric pH
`Gastric pH, as shown in Fig. 1, increased signifi-
`cantly onall 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 wasstatistically significant
`after the first and fifth doses (p < 0.002), At almostall
`time points, gastric pH was significantly higher with
`the 30-mg dose of lansoprazole than with the other two
`regimens (p < 0.05). Nostatistically significant differ-
`ences were evident between 15 mg lansoprazole and
`20 mg omeprazole.
`Figure 2 shows the mean gastric pH over 24hforall
`’ three regimens, including a combined preregimenpro-
`file (an averageofthe 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 lansoprazole than after the other
`two regimens.
`Pharmacokinetics
`Details of the pharmacokinetic parameters forall
`three regimens are shown in Table 1. There were no
`statistically significant differences between day I and
`day 3 in Crux Tix, tin, ot AUC (Fig. 44) for the two
`lansoprazole doses, nor was thereastatistically signif-
`the two regimens. For omeprazole, no statistically sig-
`icant difference in dose-normatized Cmax and AUC for
`nificant differences in Tmax or ty between day I and
`day 5 were observed. Differences did cxist between
`day 1 and day 5 results of other pharmacokinetic para-
`meters, including Crs, AUC (Fig. 4B), dose-normal-
`ized Cmax, 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-h pH plotted against AUC and in-
`eludes the regression curves obtained from the sig-
`moid Emax model.
`
`1200
`
`1600
`
`80
`2000
`bose THE
`Time
`FIG. 2. Mean gastric pHfor the two lansoprazole and the
`omeprazole regimeris on day 1 (A) and day 5 (B).
`
`2400
`
`400
`
`800
`
`
`
`oo Lansopmzots 30 mg
`—-— Lansopmzols 15 mg
`“O-> Omeprazole 20 mg
`
` GastricpH
`
`
`Day 1
`Day 5
`15 Days Post
`Pre-Regiman
`FIG. 1. Mean 24-h gastric pH levels. The asterisks mark
`slatistically significant differences (p < 0,002) between 30
`mg lansoprazole and 20 mg omeprazole or 15 mg lanso-
`prazole.
`:
`
`CONFIDENTIAL
`
`Page 3 of 6
`
`Serune Gastrin
`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-
`
`# Clin Gastroenreral, Vol. 24, No. 2, 1997
`
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`

`Statistically significantly higher than day 4 (p < 0.05}.
`
`men levels; there were nostatistically significant dif-
`ferences between the preregimen and postregimen gas-
`trin levels in any treatment regimen.
`Adverse Events
`Adverse events were reported by five subjects (31%)
`on the 15-mg lansoprazole regimen, six (43%) on the
`30-mg lansoprazole 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 15-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 aminotrans-
`ferase (ALT) level (27 FU/L) had elevated values (81
`TU/L) 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 he-was discontinued from the
`
`1000
`900
`800
`700
`aw«=Omeprazols 20 mg, Day 1
`600
`—h—=Omeprazole 20 mg, Day 6
`500
`400
`300
`200
`400
`
`80%
`
`El Lansoprazole 15 mg
`Lansoprazole 30 mg
`OC. Omeprazole 20 mg
`
`
`
` * %Time(24h)atSpecifladpH §se
`
`
`
`68
`
`K. G. TOLMAN ETAL.
`
`TABLE 1. Pharmacokinetic parameters for lansoprazole and omeprazole (mean + SD). .
`
`Cmax dose, normalized
`AUC dose, normalized
`
`Tmax(h)
`ty (h
`Cmax (ng/ml) AUC (ng-himl)
`([ng/ml}mg)
`([ng-h/mi¥mg}
`1620.7
`1.062043
`3354199
`623 + 287
`22.33 + 13,27
`41.53 + 19.13
`15405
`109+056
`9351+1.31
`723 + 323
`23,40 + 6.73
`48.20 + 21.53
`
`Lansoprazole, 15 mg
`
`15203
`7421.3
`
`17419
`1.6207
`
`0974033
`0624032
`
`7294385
`217140
`
`0.622032
`0.872050
`
`2174140
`16 + 1494
`
`1,871 755
`298 + 186.
`‘
`298 + 186
`695 + 3774
`
`24.30 + 12.83
`10.85 + 7.00
`
`10.85 + 7.00
`15.75 + 7.45?
`
`45.70 + 25.17
`14.90 + 9.30
`
`14,80 + 9.30
`29.75 + 18.85"
`
`.
`
`Day 1
`Day 5
`Lansoprazole, 30 mg
`Day 1
`Day 5
`Omeprazole, 20 mg
`Day +
`Day 5
`
`i
`i
`
`",
`-
`
`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 IU/L,re-
`spectively. After the fifth dose of 30 mg lansoprazole,
`values were 57 and 108 IU/L,respectively; by the post-
`treatment examination, AST/ALT values had decreased
`to 30 and 45 IU/L,respectively.
`
`
`
`Lansoprazole(ng/mL)
`
`4000
`900
`800
`700
`600
`
`o88888
`
`
`
`Gmeprazole(ng/mL)
`
`A. Lansoprazole
`
`gong
`
`Lansoprazote 15 mg. Day 1
`Lansoprazole 15 mg, Day 5
`Lansoprazole 30 mg, Day 1
`Lansoprazole 30 mg, Day &
`
`- Hours
`
`1i
`
`
`
`==
`
`B. Omeprazole
`
`==
`
`pH>3
`
`pH>4
`
`pH>5
`
`FIG. 3. Mean percentageof time gastric pH was >3, >4,
`and >5 on day 5. The asterisks mark statistically signifl-
`cant differences (p < 0.01) between 30 mg lansoprazole
`and the other two regimens.
`
`Hours
`
`i
`
`FIG. 4, Mean plasma concentrations of lansoprazole (A)
`and omeprazole (B) on days 1 {A} and 5 (B).
`
`J Clin Gastroenterol, Val. 24, No. 2. 1997
`
`CONFIDENTIAL
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`

`
`
`EFFECT OF LANSOPRAZOLE AND OMEPRAZOLE ON GASTRIC PH
`
`68
`
`
`
`8 7 6
`
`&e 53
`
`2=
`
`4™
`53
`2
`
`@ Lansoprazole, Day 5
`.
`© Omeprazole, Day §
`
`——— Lansopraze Sigmold Emax, Day 5.
`
`coco Omeprazole Sigmoid Emax, Day 5
`
`
`0
`
`500
`
`«1000
`
`«2000
`
`2500
`
`3000
`
`3500
`
`«61500
`AUC
`
`of the H+/K+-ATPase,it is likely that the higher gas-
`tric 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 ofraising 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 healingrates after 2, 4, and 8 weeks
`of treatment, although the correlation was less marked
`than for duodenal ulcer. In reflux esophagitis, Bell et
`al. (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 ulceris 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-
`cating a relationship between healing and degree of
`acid suppression (31,32). 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 shown -effi-
`cacy in the treatment of GERD (32-34). The dose-re-
`lated suppression ofgastric 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 levels.
`Serum gastrin increased more with the 30-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 I5 days of discontinuing medication. The
`magnitude of changes and their return to preregimen
`levels are similar to findings of other published stud-
`
`# Clin Gastroenterol, Vol. 24, Ne. 2, 1997
`
`FIG. 5. Day 5 mean 24-h pH versus AUC sigmoid Emax
`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 Cnax
`and AUC values were not different for the two doses of
`lansoprazole, With omeprazole, Ca, and AUC levels
`were significantly higher on day 5 than on day I, an ef-
`fect also described by Clissold and Campoli-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 equa! 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 whethera 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
`
`TABLE2. Mean fasting serum gasirin levels (pg/ml
`15 mg
`30 mg
`20mg
`Lansoprazole
`Lansoprazole
`Lansoprazole
`
`Timea point
`
`33.4
`41.20
`33.7
`Preragimen
`427
`45.3
`40.3
`Day 1
`59.2 |
`59.3
`52.9
`Day 5
`
`15 Days after regimen 34.6 37.7 32.1
`
`
`“1 h betora badtime.
`"Significantly higher tha 15 mg lansoprazole and 20 mg omeprazole (0
`= 0.05).
`
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`

`

`FO
`
`K. G. TOLMAN ETAL,
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`6
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`23,ae)
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`pharmacodynamic and pharmacokinetic properties and its thera-
`peutic efficacy in acid-related disorders. Drugs 1992:44-225-50,
`Dethotal-Landes B, Petite JP. Flouvat B. Clinical pharmacokinetics
`of lansoprazole. Clin Pharmacokinet 1995;28:458-70,
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`Bell NJV, Burget DL, Howden CW, etal. Appropriate acid sup-
`pression for the managementof gastro-esophageal reflux disease.
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`sophagitis: a placebo controlled trial. Gu1986;27:A609.
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`Sontag $, Kogul DG, Fleischmann R, Campbell DR, Richter J,
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`esophagitis previously resistant to H2-RA therapy. dm J Gastroen-
`terol 1996;91:1758--65.
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`37.
`
`—Olleeeeee
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`PZ00103629
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`WVIM0184259
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`Patent Owner Ex. 2034
`Mylan v. Pozen
`IPR2017-01995
`
`ies using lansoprazole (34-37). In light of the correla-
`tion ‘between increased gastric pH and healing of acid
`peptic ulcer disease and GERD,
`the results of our
`study show that, like omeprazole, lansoprazoleis a po-
`tent inhibitor of acid secretion. It also is an effective
`treatment for ducdenalulcer, gastric ulcer, and GERD.
`
`Acknowledgment: This study was supported by 2 grant from
`TAP Pharmaceuticals, Deerfield, Illinois,
`
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`J Clin Gastroenterol, Vol. 24, No. 2, 1997
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`CONFIDENTIAL
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`Patent Owner Ex. 2034
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`IPR2017-01995
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