JCIin Gartroenlerol I997;Z4(2):65 70.
`
`© 1997 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. Ringham, Ph.D.
`
`We compared gastric 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
`each given 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 under the
`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 Cmax 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-Lansoprazole—0mepra-
`zo1e—Pharmacol<ineties—Pharmaeodynamics —Gastric pl-1—
`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.,
`K.N.B.), Salt Lake City, Utah; and Abbott Laboratories (M.D.K., D.E.J.,
`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,
`4R1 18 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-
`tential for toxicity based on these interactions. For ex-
`ample, omeprazole inhibits the hepatic metabolism of
`diazepam (1-3), carbamazepine (4), antipyrine and
`aminopyrine (5), 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
`(10-1 1), or low-dose oral contraceptives (12). Theo-
`phylline clearance is marginally increased with both
`drugs (13-14). Bioavailability of the two drugs after
`oral dosing also appears
`to differ:
`lansoprazole
`bioavailability after oral closing (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—onc 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, 19-10 years), a mean height
`of 71 inches (range, 6&76 inches), and a mean weight of 173.4
`lb (range, 141-224 lb). 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 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 15 and 30 mg lansopra-
`zole and 20 mg omeprazole. The selected doses were those ap-
`
`Page 1
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`Dr. Reddy's Exh. 1057
`
`l I l 1 l
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`Page 1
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`Dr. Reddy's Exh. 1057
`
`

`
`66
`
`K. G. TOLMAN ET AL.
`
`proved by the U.S. Food and Drug Admini stration. Each treat(cid:173)
`ment period lasted 5 days, with a 2-week washout period be(cid:173)
`tween
`treatments. Postdosing evaluations were conducted
`14- 16 days after the last dose of each treatment (hereafter re(cid:173)
`fe rred to as 15 days post-treatment).
`Subjects were confined to the Drug Research Center at the
`University of Utah during the dosing peri ods, from the time be(cid:173)
`fo re dinner on day -3 to the morning of day 6, so that 24-h am(cid:173)
`bulatory pH recordings could be made under controlled condi(cid:173)
`tions. Standardized meals were given at 9: 00 a.m. , I :00 p.m. ,
`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. ( I h before breakfast).
`Safety evaluation included monitoring of adverse events, vi(cid:173)
`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(cid:173)
`bly related to treatment. Yitai signs were recorded daily during
`confinement and aga in at postdosi ng; laboratory evaluations
`were done on days I and 6, and postdosing, interim physical ex(cid:173)
`aminations were perfo rmed on days -2 and 5, and ECGs were
`recorded on day 5 and postdosing. Serum gastrin levels were
`measured fro m samples coll ected I h before and I h after meals
`on days -2, I, and 5; 15 days post-treatment; and at the end of
`each 24-h gastric pH recording period (days - I, 2, and 6 and 15
`days post-treatment) . Gastrin was measured using a double an(cid:173)
`tibody technique (Product KGA D-2, Gastrin Double Antibody;
`Diagnostic Products Corporation, Los Angeles, CA, U.S.A .).
`
`Pharmacodynamic Evaluation
`During each crossover period, ambul atory 24-h gastric pH
`was monitored on days -2, I, and 5 and on day 15 post-treat(cid:173)
`ment. A monocrystalline antimony electrode (Synectics Med(cid:173)
`ica l Inc. , Irving, TX) was positioned in the stomach before the
`start of pH recording. Electrode placement in the stomach was
`confi rmed by a drop in pH during introduction of the electrode.
`The electrodes were connected to a Digitra pper Mark IJ single(cid:173)
`channel recorder (Synectics Medical Inc.), which was cali(cid:173)
`brated before each use with buffe r solutions at pH I and 7. On
`days I and 5 of each crossover peri od, monitoring began imme(cid:173)
`diately after drug admini stration and continued every 4 s fo r 24
`h. Values were digitized and stored by the Digitrapper unit. The
`median of each l 5-min period was ca lculated fo r analysis.
`
`Pharmacokinetic Evaluation
`On days I and 5 of each treatment period, blood samples
`were drawn at several time interva ls: immediately before dosing
`and at 0.5, I, 1.5, 2, 3, 4, 6, 8, and 12 h after dosing. Venous
`pl asma samples were analyzed fo r lansoprazole and omeprazole
`using validated high-perfo rmance liquid chromatography meth(cid:173)
`ods ( 18). The following model-independent pharmacok inetic
`parameters were evaluated: individual plasma concentrations,
`peak concentration (Cmax), time to peak concentration (Tmax),
`and area under the plasma concentration curve (AUCo.-). Elim(cid:173)
`ination half- li fe (t112) was estimated based on linear regression
`of a log-tra nsfo rmed concentration of the terminal phase of the
`individual plasma concentrations. Comparisons were not made
`between lansoprazole and omeprazo le because clinical rather
`than identical doses were given.
`
`Statistical Analysis
`
`Gastric pH
`All statistical tests were two-tailed, with significance des ig(cid:173)
`nated asp :o; 0. 05. The preregi men value was the value obta ined
`
`J C/in Gastroenterol. Vol. 24. No. 2. 1997
`
`before each treatment regimen (day -2); the postregimen value
`was that obtained 14- 16 days after completion (day 15 post(cid:173)
`treatment). The 15-min median pH values fo r each subj ect were
`used fo r 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 perfo rmed over the total
`24-h period as well as over fo ur specified time intervals
`(0800- 1300, 1300- 1800, 1800-2300, and 2300-0800 h). The
`onset of action was examined similarly on an hourly basis, with
`time to effect described as the first hour in which significant
`diffe rences from baseline were noted.
`For each evaluation day, the effects of the three regimens on
`gastric pH variables were compared wi th a crossover model that
`included regimen, period, sequence, and subj ects within se(cid:173)
`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
`fra mework of this model, pairwise comparisons were made of
`day I versus preregimen, day 5 versus preregimen, day 5 versus
`day I, and day 15 post-treatment versus preregimen.
`
`Pharmacokinetics
`Analyses of variance were performed fo r lansoprazole and
`omeprazole pharmacokinetic parameters. For lansoprazole, the
`fo llowing effects were included in the model: period, subject,
`dose, day, period-by-day interaction, and dose-by-day interac(cid:173)
`tion. For omeprazole, the effects included were period, subject
`nested within period, and day. The Cmax and AUC values from
`the 30-mg lansoprazole regimen were normalized to a 15-mg
`dose to j udge dose proportionality.
`
`Relationship of AUC to Gastric pH
`Analysis of covariance was employed to explore the relation(cid:173)
`ship between 24-h average gastric pH and plasma AUC for lan(cid:173)
`soprazole and omeprazole. The dependent variable was average
`pH; the covariate was the natu ral logari thm of AUC. For lanso(cid:173)
`prazole, an analysis was performed fo r data on days I and 5
`jointly, with effects fo r period, day, subject, day-by-subject in(cid:173)
`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 concentrati on AUC was
`also examined using a sigmoidal Emax model ( 19- 2 1 ).
`
`Serum Gastrin
`Gastrin values were measured I h before and after each meal
`on day -2 (preregimen), days I and 5, and day 15 (post-treat(cid:173)
`ment) fo r each of the three regimens. An additional measure(cid:173)
`ment was obtained 14 h after dinner. Gastrin variables analyzed
`included values at each of these time points as well as integrated
`gastri n, defined as the area under the gastrin curve fro m I h be(cid:173)
`fo re breakfast to I h after dinner (0800- 1900), as calcu lated by
`the trapezoidal method. Changes fro m preregimen serum gas(cid:173)
`trin va lues were analyzed between and within regimens using
`the crossover and repeated-measures model, respective ly.
`
`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 COSTA RT term and body system. Changes
`fro m preregimen clinical laboratory variables and vital signs
`were compared using the crossover model d.escribed fo r gastric
`pH ; changes in ECG and results of physical exam ination were
`reviewed and tabulated.
`
`Page 2
`
`Dr. Reddy's Exh. 1057
`
`

`
`EFFECT OF LANSOPRAZOLE AND OMEPRAZOLE ON GASTRIC PH
`
`6 7
`
`A. Day 1
`
`.......... Combined Pie-Regimen
`Lansoprazole 15 mg
`Lansoprazole 30 mg
`......... .. Omeprazole 20 mg
`A fime of Meals
`
`GastricpHI0(4015U‘!G)\lG)
`
`Mean
`
`1200
`
`1 600
`
`800
`DOSE TIME
`
`2000
`Time
`
`2400
`
`400
`
`800
`
`B. Day 5
`
`.......... Combined Pre—l-Regimen
`Lansoprazole 15 mg
`Lansoprazole 30 mg
`......... .. Omeprazole 20 mg
`A Time of Meals
`
`
`
` MeanGastricpH
`
`...___:_:-_J I
`
`1
`
`‘*5;
`
`\ 8
`
`00
`DOSE TIME
`
`1200
`
`1600
`
`2000
`Time
`
`2400
`
`400
`
`800
`
`FIG. 2. Mean gastric pH for the two lansoprazole and the
`omeprazole regimens on day 1 (A) and day 5 (B).
`
`the two regimens. For omeprazole, no statistically sig-
`nificant differences in Tm“ or t1/2 between day l 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,-M, and dose-normalized AUC, all of which
`were higher on day 5 than on day l (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-
`cludes the regression curves obtained from the sig-
`moid Emax model.
`
`Serum Gastrin
`
`Increases in serum gastrin levels from prcrcgimen
`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—
`
`JClin Gastroenterol, Vol. 24, Na. 2, 1997
`
`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
`after the first and fifth doses (p S 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 (in < 0.05). No statistically significant differ-
`ences were evident between 15 mg lansoprazole 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 <0.0l) 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 for all
`three regimens are shown in Table 1. There were no
`statistically significant differences between day l and
`day 5 in Cniax, Tm,“ ti/2, or AUC (Fig. 4A) for the two
`lansoprazole doses, nor was there a statistically signif-
`icant difference in dose-normalized Cmax and AUC for
`
` -0- Lansoprazole 30 mg
`
`-I— Lansoprazole 15 mg
`Omeprazole 20 mg
`
`GastricpH
`
`Pre-Regimen
`
`Day 1
`
`Day 5
`
`15 Days Post
`
`FIG. 1. Mean 24-h gastric pH levels. The asterisks mark
`statistically significant differences (p 5 0.002) between 30
`mg lansoprazole and 20 mg omeprazole or 15 mg lanso-
`prazole.
`
`Page 3
`
`Dr. Reddy's Exh. 1057
`
`Page 3
`
`Dr. Reddy's Exh. 1057
`
`

`
`68
`
`K. G. TOLMAN ET AL.
`
`TABLE 1. Pharmacokinetic parameters for lansoprazole and omeprazo/e (mean± SD)
`
`T max (h)
`
`t ·,, (h)
`
`Cmax (ng/ml)
`
`AUC (ng · h/ml)
`
`Cmax dose, normalized
`([ng/ml)/mg)
`
`AUC dose, normalized
`([ng· h/ml]/mg)
`
`Lansoprazole, 15 mg
`Day 1
`Day 5
`Lansoprazole, 30 mg
`Day 1
`Day 5
`Omeprazole, 20 mg
`Day 1
`Day 5
`
`1.6 ± 0.7
`1.5 ± 0.5
`
`1.06 ± 0.43
`1.09 ± 0.56
`
`335 ± 199
`351±1 .31
`
`623 ± 287
`723 ± 323
`
`1.5 ± 0.3
`1.7±1.3
`
`0.97 ± 0.33
`0.62 ± 0.32
`
`729 ± 385
`217±140
`
`1,371 ± 755
`298 ± 186
`
`1.7±1 .3
`1.6 ± 0.7
`
`0.62 ± 0.32
`0.87 ± 0.50
`
`217±140
`315 ± 1498
`
`298 ± 186
`595 ± 377•
`
`22.33 ± 13.27
`23.40 ± 8.73
`
`24.30 ± 12.83
`10.85 ± 7.00
`
`10.85 ± 7.00
`15.75 ± 7.45 8
`
`41 .53 ± 19.13
`48.20 ± 21 .53
`
`45.70 ± 25.17
`14.90 ± 9.30
`
`14.90 ± 9.30
`29.75 ± 18.85•
`
`•Statistically significantly higher than day 1 (p < 0.05) .
`
`men levels; there were no statistically significant dif(cid:173)
`ferences between the preregimen and postregimen gas(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`ferase (ALT) level (27 IU/L) had elevated values (81
`IU/L) just before dosing with 15 mg lansoprazole; on
`day 4 of the first crossover period, his ALT had in(cid:173)
`creased to 224 IU/L, and he was discontinued from the
`
`(/)
`
`::c:
`a.
`"tl
`~ ·c:;
`GI a.
`iii
`:2
`"2"
`~
`GI
`E
`i=
`:J! 0
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`D Lansoprazole 15 mg
`•
`Lansoprazole 30 mg
`D Omeprazole 20 mg
`
`pH> 3
`
`pH> 4
`
`pH >5
`
`FIG. 3. Mean percentage of time gastric pH was >3, >4,
`and >5 on day 5. The asterisks mark statistically signifi(cid:173)
`cant differences (p :::; 0.01) between 30 mg lansoprazole
`and the other two regimens.
`
`J Clin Gastroenterol, Vol. 24. No. 2. 1997
`
`study after testing positive for hepatitis C. Another sub(cid:173)
`ject had elevated AST/ALT values attributed to study
`drugs at the end of each crossover period. His pretreat(cid:173)
`ment AST and ALT levels were 30 and 36 IU/L, re(cid:173)
`spectively. After the fifth dose of 30 mg lansoprazole,
`values were 57 and 108 IU/L, respectively; by the post(cid:173)
`treatrnent examination, AST/ALT values had decreased
`to 30 and 45 IU/L, respectively.
`
`1000
`900
`::J
`800
`E
`"Ci 700
`.s
`600
`GI
`N .,
`0
`500
`ii 400
`0
`.,
`<I) c
`300
`..J
`200
`100
`0
`
`1000
`900
`::J 800
`E 700
`"Ci .s
`600
`~
`N .,
`500
`0
`ii 400
`GI
`E 300
`0
`200
`100
`0
`
`A. Lansoprazole
`
`--D-
`-9-
`-0-
`-+-
`
`Lansoprazole 15 mg, Day 1
`Lansoprazole 15 mg, Day 5
`Lansoprazole 30 mg, Day 1
`Lansoprazole 30 mg, Day 5
`
`0
`
`2
`
`4
`
`6
`Hours
`
`8
`
`10
`
`12
`
`B. Omeprazole
`
`-ts- Omeprazole 20 mg, Day 1
`_....._ Omeprazole 20 mg, Day 5
`
`0
`
`2
`
`4
`
`6
`Hours
`
`8
`
`10
`
`12
`
`FIG. 4. Mean plasma concentrations of lansoprazole (A)
`and omeprazole (B) on days 1 (A) and 5 (B).
`
`Page 4
`
`Dr. Reddy's Exh. 1057
`
`

`
`EFFECT OF LANSOPRAZOLE AND OMEPRAZOLE ON GASTRIC PH
`
`69
`
`
`
`Mean24HourpH 5
`
`FIG. 5. Day 5 mean 24-h pH versus AUC sigmoid Ernax
`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 Cm,
`and AUC values were not different for the two doses of
`
`lansoprazole. With omeprazole, Cmax and AUC levels
`were significantly higher on day 5 than on day 1, 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 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/mI)a
`
`Time point
`
`15 mg
`Lansoprazole
`
`30 mg
`Lansoprazole
`
`20 mg
`Lansoprazole
`
`33.7
`40.3
`52.9
`37.7
`
`Preregimen
`Day 1
`Day 5
`15 Days after regimen
`51 h before bedtime.
`“Significantly higher the 15 mg lansoprazole and 20 mg omeprazole (p
`g 0.05).
`
`41.2”
`45.3
`59.3
`32.1
`
`33.1
`42.7
`59.2
`34.6
`
`Page 5
`
`Dr. Reddy's Exh. 1057
`
`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 rcflux 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. ln 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 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-
`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 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 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 15 days of discontinuing medication. The
`magnitude of changes and their return to preregimen
`levels are similar to findings of other published stud-
`
`JClin Gaxtroenterol. Vol. 24, Na. 2, 1997
`
` I Lansoprazole, Day 5
`
`
`O Omeprazole, Day 5
`Lansoprazole Slgmold Emax, Day 5
`- - - - - Omeprazole Sigmoid Emax. Day 5
`
`
`
`0
`
`500
`
`1000
`
`
`
`2000
`
`2500
`
`3000
`
`3500
`
`1500
`AUC
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`Page 5
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`Dr. Reddy's Exh. 1057
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`

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`70
`
`K. G. TOLMAN ET AL.
`
`ies using lansoprazole (34-37). In light of the correla(cid:173)
`tion between increased gastric pH and healing of acid
`peptic ulcer disease and GERD, the results of our
`study show that, like omeprazole, lansoprazole is a po(cid:173)
`tent inhibitor of acid secretion. It also is an effective
`treatment for duodenal ulcer, gastric ulcer, and GERD.
`
`Acknowledgment: This study was supported by a grant from
`TAP Pharmaceuticals, Deerfield, Illinoi s.
`
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