GASTROENTEROLOGY 1985;88:64—9
`
`Omeprazole: A Study of Its Inhibition of
`Gastric pH and Oral Pharmacokinetics
`After Morning or Evening Dosage
`
`PETER I. PRICHARD, NEVILLE D. YEOMANS,
`GEORGE W. MIHALY, D. BRIAN JONES, PETER ]. BUCKLE,
`RICHARD A. SMALLWOOD, and WILLIAM J. LOUIS
`Departments of Gastroenterology and Clinical Pharmacology/Tlierapeutics, Division of Medicine,
`University of Melbourne, Austin Hospital, Heidelberg. Victoria, Australia and Astra
`Pharmaceuticals, North Ryde 2113. New South Wales, Australia
`
`Pharmacodynamic and pharmacokinetic studies of
`omeprazole, a new gastric antisecretory agent, were
`undertaken in 8 healthy subjects. The drug was
`administered orally as an encapsulated enteric-
`coated granulate {40 mg daily at 9 AM or 9 PM for 5
`days), and its effect on the integrated 24-h gastric pH
`was determined, together With its apparent bioavail-
`ability. The pretreatment 24-h median pH was 1.9
`(interquartile range 1.4e2.9), After 5 days of treat-
`ment, the median pH had risen to 5.0 (3776.0) {p <
`0.01) with morning dosage and 4.5 {3.0~5.6J (p <
`0.01} with evening dosage. This corresponded to (1
`>99% reduction in 24-h median hydrogen ion activ-
`ity, with morning dosage having a greater effect
`[from 9 AM to 8 PM] (p < 0.01) than evening dosage.
`The relative bioavailability of omeprazole increased
`twofold from day 1
`to day 5 of treatment with
`morning dosage {p < 0.02) and threefold with eve»
`ning dosage {p < 0.02). suggesting that increased
`absorption of this acid-labile drug occurs with in-
`creasing inhibition of acid secretion. We conclude
`that this formulation of omeprazole presently being
`used in clinical trials is a highly potent antisecretory
`
`Received January 23, 1984. Accepted Iuly 16. 1984.
`Address requests for reprints to: Neville D. Yeomans, M.D.,
`Gastroenterology Unit, Department of Medicine. Austin Hospital,
`Heidelberg 3084, Victoria. Australia.
`This work was supported by the National Health and Medical
`Research Council of Australia,
`A preliminary communication of part of this work has appeared
`as an abstract [1) and was presented at
`the Annual Scientific
`Meeting of the Gastroentemlogical Society of Australia, Perth,
`Australia, May 1983.
`The authors thank Dr. lohn McNeil for help with computer
`processing.
`© 1985 by the American Gastroenterological Association
`0016~5085/85!$3.30
`
`agent in humans, although its optimal effect may not
`be observed for several days.
`
`Omcprazole, a substituted benzimidazole. is a potent
`long—acting inhibitor of gastric acid secretion [2).
`Omeprazole has been shown to act by inhibition of
`H+,K+—adenosine triphosphatase, a proton pump
`that seems to be peculiar to the gastric parietal cell
`[3—7]. The initial clinical studies of omeprazole
`appear promising in that the drug has been shown to
`promote duodenal ulcer healing [8,9], and to control
`ZollingeriEllison syndrome symptoms when other
`drugs have failed [IO—12). To date there is little
`information about the antisecretory activity of ome-
`prazole in humans [2,13,14], and human pharmaco-
`kinetic data of this drug are restricted to those
`obtained using a single dose of a buffered suspension
`or an encapsulated uncoated granulate given with
`liquid buffer (2,14). As omeprazole is acid-labile,
`unprotected exposure to acidic gastric contents re-
`sults in inactivation of >50% of an oral dose (Skan-
`berg I, personal communication]. Thus the formula—
`tion of the oral preparation will have a profound
`effect on the pharmacokinetics, and on the antisecre—
`tory effect of the drug.
`In the present study we have examined the oral
`pharmacokinetics and the gastric antisecretory activ-
`ity of omeprazole formulated as an encapsulated,
`enteric-coated granulate, which is the form currently
`undergoing clinical trial
`[8]. Two particular ques-
`tions have been considered: [a] whether morning or
`evening administration of a daily 40-mg dose gives
`better control of 24-h intragastric pH, and (b) wheth-
`er the oral bioavailability of this formulation in-
`creases during the initial phase of treatment as acid
`secretion declines.
`
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`Dr. Reddy's Exh. 1056
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`

`

`
`OMEPRAZOLE: DYNAMICS AND KINETICS 65
`
`Material and Methods
`
`Subjects
`
`Eight healthy male volunteers were studied. Mean
`age was 22 yr [range 20—26 yr], and mean weight was 74 kg
`[range 63—116 kg). None were smokers, and none had a
`It history of peptic ulcer disease. Physical examination,
`' electrocardiogram, and laboratory screen were normal
`. before inclusion.
`Informed written consent was given by all subjects, and
`the study was approved by the Human Experimentation
`Committee of the University of Melbourne on November
`24, 1982.
`
`Drug
`
`Omeprazole is a crystalline solid that is chemically
`labile and rapidly degraded in acidic media. It was there-
`fore administered as an encapsulated, enteric-coated gran-
`ulate (each capsule containing 20 mg of omeprazole]. Drug
`and matching placebo capsules were provided by Astra
`Pharmaceuticals [North Ryde, Australia).
`
`Study Design
`
`Patients were admitted to a special hospital ward
`on five occasions for 24—h gastric pH or pharmacokinetic
`studies, or both. Meals and fluid intake were identical
`during each study day. Small meals and snacks were given
`at 8 AM, 11 AM, 4 PM, and 11 PM, and main meals were given
`at 12 noon and 6 PM. The patients were not confined to
`bed, but maintained normal daily activity within the
`confines of the study area.
`Subjects first underwent a baseline study of gastric pH
`(day 0], during which placebo capsules were given at 9 AM
`and 9 PM. Thereafter, the subjects were randomly assigned
`to one of two treatment groups. The first group initially
`received omeprazole [40 mg) at 9 AM and placebo at 9 PM.
`The second received placebo at 9 AM and omeprazole at
`9 PM. Each group took their medication at the specified
`times for 5 days (period 1), followed by a 15—day washout
`period when no medication was administered. The sub-
`jects were then crossed over to the alternative dosage
`schedule for a further 5 days of medication [period 2).
`Food was withheld for 1 h before and 2 h after capsule
`administration. On day 1 of each period, subjects under-
`went a pharmacokinetic study. On day 5 of each period,
`they were again studied in the hospital, with measurement
`of both pharmacokinetics and gastric pH. During the
`intervening days at home the subjects continued to eat
`meals at similar times to those during the hospital study
`days.
`
`Gastric pH Studies
`
`Each subject was intubated at 7 AM with a 10F
`nasogastric Salem sump tube [Argyle, St. Louis, Mo.),
`which was positioned, under fluoroscopic control, in the
`most dependent part of the stomach. Samples [2 ml) of
`gastric juice were aspirated hourly throughout the day
`from 8 AM until 9 AM on the following day. The pH of each
`
`sample was immediately determined using a glass elec-
`trode and digital pH meter [Orion Research model 611,
`Orion Research Inc., Cambridge, Mass}. The pH meter was
`calibrated with Merck standard buffers (E. Merck, Darm-
`stadt, West Germany) at pH 2.0 and pH 7.0. and linearity of
`the slope was verified at pH 4.0. The calibration was
`checked at regular intervals and varied by <0.1 pH units
`during the course of the day. Hydrogen ion activity was
`calculated by direct conversion of pH to millimoles per
`liter of free hydrogen ions.
`
`Pharmacokinetic Studies
`
`Each subject had an intravenous cannula inserted
`into a forearm vein at 7:1 5 AM. Five milliliters of blood was
`collected into a heparinized tube, before the omeprazole or
`placebo dose, and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,
`6.5, 7, 8, 10, and 12 h postdose. Samples were immediately
`centrifuged for 5 min and the plasma was transferred to
`plastic tubes containing 10 jul of 1 M Na2C03. Urine
`samples were also collected predose, and for the period 0—
`12 h postdose. At the end of each collection period, urine
`pH and volume were determined, and a 5-ml aliquot was
`added to a plastic tube containing 20 ul of 1 M Na2C03. All
`samples of plasma and urine were stored at 720°C.
`
`Drug Assays and Pharmacokinetic
`Calculations
`
`Plasma and urine samples were assayed for ome-
`prazole and for two of its metabolites, omeprazole sulfone
`and omeprazole sulfide, using a high pressure liquid
`chromatographic method (15). Sensitivities were 5, 30,
`and 50 ng/ml for omeprazole, omeprazole sulfone, and
`omeprazole sulfide, respectively. The corresponding coef-
`ficients of variation were 4%, 7%, and 17%.
`Areas under the plasma concentration-time curve from
`time 0 to either the last detectable plasma level [C,) or 12 h
`(Ct=C12) [AUCM] were determined using the linear trape—
`zoidal rule [16). In all studies plasma levels of omeprazole
`were undetectable at time zero, so that there was no need
`to correct for residual drug in the AUC calculations after
`repeated dosage. The ratios of AUCM on day 5 to that on
`day 1 were taken as a measure of relative bioavailability
`(16]. Peak concentration (Cpkj and time to peak concentra-
`tion (Tm) were calculated directly from the plasma con-
`centration data for each individual. Apparent elimination
`half-life [tjjzfi] was calculated where possible by regression
`of the log-linear portion of the plasma elimination phase.
`
`Safety Evaluation
`
`On each hospital study day, pulse rate, blood
`pressure, and electrocardiogram were monitored at fre-
`quent intervals, and patients were questioned about ad-
`verse symptoms. A laboratory screen that included plasma
`urea and electrolytes, hepatic enzymes, thyroid function
`tests, hemoglobin, hematocrit, differential white cell
`count, platelet count, and urinary analysis was performed
`before the baseline day, and 7 and 28 days after the last
`omeprazole dose.
`
`Page 2
`
`Dr. Reddy's Exh. 1056
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`Dr. Reddy's Exh. 1056
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`

`

`
`
`66 PRICHARD ET AL.
`
`GASTROENTEROLOGY Vol, 88, No. 1, Part
`
`1
`
`Statistical Analysis
`
`Because of significant skewness [17] of the distri-
`butions of pH and hydrogen ion activity, these data have
`been presented not as means and standard errors but as
`medians with interquartile ranges. The median was a more
`representative measure of central
`location, or in other
`words of “average value,” than either the ordinary arith—
`metic mean or the geometric mean [arithmetic mean of log—
`transformed data). Other data that were normally distribut—
`ed are presented. as usual, as mean : SEM. Gastric pH and
`hydrogen ion activity were compared using distribution-
`independent nonparametric methods (Wilcoxon’s signed-
`ranks test) [17]. Before applying these methods, the hourly
`data of a subject were summarized into one value [median]
`for the time period being evaluated [18]. Determination of
`significant differences in other data was made using paired
`Student’s t-tests [17]. A value of p < 0.05 was regarded as
`significant.
`
`Results
`
`Gastric Acidity Studies
`
`The patterns ‘of gastric pH over 24 h, before
`and on day 5 of treatment with omeprazole, taken
`either in the morning or evening, are shown in
`Figure 1. The gastric pH throughout the 24 h was
`substantially higher with both regimens of active
`omeprazole administration than on the control day
`(p < 0.01, Wilcoxon's signed-ranks test]. The median
`pH’s over this period were 5.0 and 4.5 for morning
`and evening dosage, respectively, and 1.9 for the
`control study.
`When the pH—time profiles were divided into two
`12-h periods, the median pH after morning dosage of
`omeprazole was 5.4 in the period from 9 AM to 8 PM
`and 4.5 from 9 PM to 8 AM. After evening dosage, the
`
`pH
`
`Gaslllc
`
`0900
`
`mm
`
`mm
`
`mm
`
`0100
`
`0500
`
`0900
`
`Tlm.
`
`(h on In)
`
`Figure 1. Gastric pH-time profiles for the baseline study [open
`triangles] and after 5 days of omeprazole administra»
`tien in the morning [closed Circles] or evening (open
`Circles]. Values are medians with interquartile ranges
`[n z 8]. Closed triangles, dosage times [omeprazole
`or placebo]: closed stars. main meals; open stars, small
`meals and snacks.
`
`Table 1. Gastric pH and H' Activity, Medians, and
`Other Population Parameters for the 24-Hour
`Period
`
`Interquartile Arithmetic
`
`Median
`range
`mean :- SD skewness
`
`1.9
`5.0
`4.5
`
`1.4-2.9
`3.7410
`3.0—5.6
`
`2.3 t 1.2
`4.8 i 1.4
`4.4 r 1.7
`
`1.22“
`70411)
`—0.00
`
`pH
`Baseline
`Morning dose
`Evening dose
`H‘ activity
`(mmnl/h]
`1.47"
`26.1 1 32.9
`13—398
`12.6
`Baseline
`4.24"
`1.1 t 3.3
`0.001702
`001
`Morning dose
`
`Evening dose 3.86“ 0.04 0003—10 3.7 i 10.3
`
`
`
`a p < 0.001. b p < 0025.
`
`Page 3
`
`Dr. Reddy's EXh. 1056
`
`corresponding median pH’s were both 4.3. Thus,
`morning dosage resulted in a higher gastric pH
`during the period from 9 AM to 8 PM (p < 0.01,
`Wilcoxon’s signed-ranks test], but from 9 PM to 8 AM
`the control of gastric pH was similar with both
`morning and evening administration of omeprazole.
`One measure of the usefulness of gastric antisecre-
`tory drugs is the proportion of the day during which
`the pH of gastric juice is kept above the activity range
`of pepsin [i.e.,
`to pH 2 5.0]. During the control
`study,
`the gastric pH was 2 5.0 in only 3% of
`determinations [taken every 60 min], in contrast to
`51% with morning and 34% with evening dosage
`administration.
`
`When pH values were converted to hydrogen ion
`activities, the 24-h medians during day 5 of omepra—
`zole treatment were 0.01 and 0.04 mmol/L for morn—
`ing and evening dosage, respectively, compared with
`12.6 mmol/L for the control study. For both omepra-
`zole regimens this represents inhibition of hydrogen
`ion activity of >99%.
`The principal gastric pH and hydrogen ion activity
`data are summarized in Table 1. The highly signifi-
`cant skewness values and the large differences be-
`tween variances of the individual groups [Bartlett’s
`test, pH data: )8 = 20.6 [p < 0.001]; hydrogen ion
`activity: X2 2 744.1 [p < 0001)] indicate that the
`data are not normally distributed and are, therefore,
`not appropriately expressed as mean : SD. Howev—
`er. to allow comparison with other studies [13,19]
`the arithmetic mean has been included in Table 1.
`
`Pharmacokinetic Studies
`
`The mean plasma concentration-versus—time
`profiles for omeprazole on days 1 and 5 after morn-
`ing and evening dosage are shown in Figure 2.
`Pharmacokinetic parameters for omeprazole and one
`of its metabolites, omeprazole sulfone, are summa-
`rized in Table 2. The second metabolite, omeprazole
`
`
`
`Page 3
`
`Dr. Reddy's Exh. 1056
`
`

`

`January 1985
`
`OMEPRAZOLE: DYNAMICS AND KINETICS 67
`
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`Figure 2. Plasma concentration-time curves for omeprazole (40
`mg] on day 1 and day 5 of dosage. given AM or PM.
`Values are the mean concentration with SEM (n : 8].
`
`sulfide. was infrequently detected in plasma, and
`was not subjected to pharmacokinetic analysis.
`Between day 1 and day 5 of omeprazole dosage,
`given either in the morning or the evening, there was
`a significant increase in the area under the omepra-
`zole plasma concentration—time curve [AUC.,_,] (p <
`0.02]. and also in the peak plasma concentration
`achieved [p < 0.05]. This increase in AUC over 5
`days, which occurred in every subject (Figure 3],
`represents a 19-fold increase in relative bioavailabil-
`ity with morning dosage and a 2.9-fold increase with
`evening dosage.
`therapy the time to peak plasma
`On day 1 of
`concentration was shorter [p < 0.02], peak concen-
`tration was higher [p < 0.01], and AUC was greater
`[p < 0.05] with morning dosage. On day 5, however,
`the differences in these parameters between morning
`and evening dosage were no longer statistically sig-
`nificant.
`Elimination half-lives [tlsz] of omepazole could
`not be characterized in eight of thirty-two plasma
`concentration profiles because of erratic and contin-
`
`5000
`
`do”
`
`3000
`
`2000
`
`1000
`
`ng.h./ml
`
`It]<\\ l\\
`
`STUDY DAV :
`P.H.
`AJI.
`DOSE TIME:
`Figure 3. Area under the omeprazole plasma concentration»time
`curves. Subjects are numbered for comparison of AM
`and PM studies. Horizontal bars represent mean i SEM.
`
`ued absorption of enteric-coated omeprazole during
`the elimination phase. When there was log-linear
`elimination, mm was 0.7 h [n = 8. SEM 0.1] for
`morning dosage, day 1, and 1.1 h [n = 7, SEM 0.1] for
`day 5 (p < 0.05]. For evening dosage, a similar trend
`was apparent [1.0 h day 1 vs. 1.5 h day 5).
`Plasma concentrations of omeprazole sulfone were
`greater after 5 days of omeprazole administration.
`The corresponding increases in sulfone AUC were
`2.1—fold [SEM 0.2, p < 0.01] and 39-fold [SEM 0.6,
`p < 0.02] for morning and evening dosage, respec-
`tively.
`
`
`
`Table 2. Omeprazole and Omepmzole Sulfone Pharmacokinetic Parameters After One or Five Doses of 40 mg of Oral
`__—__—__________—___—_.———————
`Omepmzole
`
`Pharmacokinetic
`Morning dosage
`Evening dosage
`parameters
`Day 1
`Day 5
`Day 1
`Day 5
`
`Omeprazole
`AUCU ,tng - h/ml]
`an (rig/ml]
`TM (ltj
`Sultnne
`2338 (585]
`871 (240]
`2556 [576]
`1286 (321]
`AUCuij (Hg 'h/ml]
`Cpk lng/ml]
`301 [60]
`486 [124]
`227 {59]
`353 [68]
`
`TpL (h)
`3.4 (0.4]
`4.5 (0.3)
`5.6 [0.6]
`4.3 (0.2}
`AUCU ,. area under plasma concentration-time curve 0 to t; CPL. peak plasma concentration; Tpk.
`time to reach peak plasma
`concentration. Values are mean : SEM.
`
`1187 (246]
`644 [110]
`3.0 [0.4]
`
`2223 (425)
`936 (177)
`2.9 [0.3]
`
`8421108]
`296 (65]
`4.8(013)
`
`23031566]
`705 [162]
`3.3 [0.5]
`
`Page 4
`
`Dr. Reddy's Exh. 1056
`
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`
`Dr. Reddy's Exh. 1056
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`

`

`68 PRICHARD ET AL.
`
`GASTROENTEROLOGY Vol, 88, No. 1, Part 1
`
`Omeprazole sulfone, but not omeprazole, was de-
`tectable in urine. On day 1, 2.7% and 6.5% of the oral
`dose was excreted for morning and evening dosage,
`respectively. Results were similar on day 5 [2.6%
`and 5.4%].
`
`sentation of gastric pH and acidity data, is in contrast
`to other studies [13,19—22]. These previous studies
`used parametric tests of significance [such as analy-
`sis of variance), and often presented data as arithme-
`tic means and standard errors. Because of the skew-
`ness
`and
`non-Gaussian
`distribution of
`these
`
`
`
`
`
`.u.___..._._..__‘-”mum
`
`parameters, the arithmetic mean 1 SEM poorly de-
`scribes the data, and the use of parametric tests is
`hazardous [17). For example, the arithmetic mean of
`pH and hydrogen ion activity respectively underes-
`timates and overestimates the point of central ten-
`dency as given by the median. In some of our data
`this discrepancy was marked.
`Gastric pH was measured after 5 days of dosage
`because the effect of omeprazole on gastric acid
`secretion reaches a plateau over this period (23].
`This may largely reflect the long half—time of inhibi-
`tion of acid secretion of 24 h [2), which is thought to
`be due to the persistence of omeprazole or metabo—
`lite within the parietal cell [4,14,24]. However, the
`delay in reaching a maximal effect on acid secretion
`is likely to be due in part to the increasing bioavail-
`ability of omeprazole over this time [Figure 3].
`One purpose of
`this study was to determine
`whether morning or evening dosage gave better con—
`trol of 24—h intragastric pH. Whereas a 40—mg dose of
`omeprazole in the evening substantially elevated
`intragastric pH throughout the day and night, the
`elevation was greater overall after morning dosage,
`due to better control of acidity during the period
`from 9 AM to 8 PM. A possible explanation is that,
`after morning dosage, intracellular concentrations of
`omeprazole were higher during the day, when there
`were more stimuli to acid secretion [e.g., meals];
`whereas after evening dosage, these concentrations
`were maximal when stimuli to acid secretion were
`
`few. This finding would suggest that morning dosage
`should be the regimen of choice for future ulcer-
`healing studies.
`Two previous reports have provided some phar—
`macokinetic information about omeprazole in hu-
`mans [2,14). In these a single dose of drug, either as a
`micronized suspension or as uncoated granules, was
`given with bicarbonate followed by repeated admin—
`istration of bicarbonate. The purpose of this method
`of dosing was to minimize intraluminal degradation
`as omeprazole is acid-labile. The time to peak plas-
`ma concentration was reported to be 30—40 min, and
`the plasma half-life averaged 50 min. In our study we
`have used an encapsulated enteric-coated granulate
`to minimize acid degradation. We found the plasma
`half-life after a single dose of the enteric-coated
`granulate to be similar to that previously reported
`[44 min for morning dosage), but as expected the
`time to peak plasma concentration was delayed to
`several hours when the enteric-coated granulate was
`used. The AUC for single dosage of this granulate
`
`1 t t
`
`Safety Evaluation
`
`Omeprazole administration produced no de-
`tectable side effects. Several subjects complained of
`a mild sore throat and tiredness at
`the end of a
`
`hospital day, but this could reasonably be attributed
`to the study procedures. There was no significant
`alteration of pulse rate, blood pressure, electrocar-
`diogram, biochemical parameters, or urinary analy-
`sis. Hematologic indices were also normal with the
`exception of slight falls in the mean erythrocyte
`count [52 to 4.8 X tow/L), hemoglobin level (146 to
`134 g/L], and hematocrit reading [0.45 to 0.41]. These
`changes [with the exception of the hematocrit read-
`ing) were within the laboratory reference range, had
`reversed by the final
`follow—up examination, and
`were attributed to blood sampling during the course
`of the study.
`
`Discussion
`
`In this study, 5 days of omeprazole treatment
`produced a marked elevation in gastric pH that was
`sustained throughout an entire day. The changes in
`24-h median pH correspond to reductions in hydro-
`gen ion activity of up to 1200-fold. This reduction in
`hydrogen ion activity assumes greater significance
`when compared with the mere twofold to tenfold
`Change that occurs with histamine Hz-receptor an-
`tagonists (19.21]. A similar effect with omeprazole
`given once daily in the morning was found in
`duodenal ulcer patients by Walt at al.
`[13] who
`obtained a median pH of 5.3, compared with our
`24-h median pII of 5.0 for morning dosage.
`The method used in the present study for assess—
`ing the antisecretory effects of omeprazole, the serial
`determination of intragastric pH over a prolonged
`period, has been used in a number of other clinical
`studies of antisecretory drugs [13,19—21]. A disad-
`vantage of this approach is that this method gives no
`information about the volume of secretion. The ad-
`
`vantage, however, is that it gives information about
`gastric acidity under conditions of diet and activity
`that approximate normal living. It also allows the
`study of the influence of dosage time on clinically
`important variables such as drug effect and pharma—
`cokinetics. The resulting information is relevant to
`the rational use of the drug in the clinical setting.
`Our use of a nonparametric method [Wilcoxon’s
`signed-ranks test) for statistical significance testing,
`and of the median with interquartile range for pre-
`
`Page 5
`
`Dr. Reddy's EXh. 1056
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`Page 5
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`Dr. Reddy's Exh. 1056
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`

`January 198 5
`
`OMEPRAZOLE: DYNAMICS AND KINETICS 69
`
`was similar to that obtained with equivalent doses of
`uncoated drug administered with bicarbonate (2,14),
`but considerably greater than after uncoated drug
`given without buffer (Skanberg I, personal communi-
`cation). In addition, it was apparent in our study that
`absorption was faster when a single dose was given
`in the morning than in the evening.
`In every subject, bioavailability of omeprazole
`
`increased during repeated dosage, coincident with
`substantial reduction in gastric acidity. This in—
`
`creased bioavailability, together with greater peak
`
`plasma concentrations, could theoretically be due to
`
`either
`increased absorption or decreased plasma
`
`clearance. In the absence of intravenous kinetic data,
`
`decreased clearance cannot be excluded, but given
`
`the acid lability of the drug it is highly likely that
`
`increased absorption is primarily responsible for the
`
`increased bioavailability.
`
`What significance can be put on plasma pharma—
`
`cokinetic data for a drug that has sustained effects on
`
`its target organ long after it is cleared from plasma?
`
`Although there is no direct temporal relationship
`
`between the plasma concentration of omeprazole
`
`and its antisecretory effect, the AUC for this drug
`
`correlates well with the magnitude of acid inhibition
`
`[2,14]. Thus the substantial increase in AUC, i.e., in
`
`bioavailability. observed in the present study is
`
`likely to be reflected in increased acid inhibition,
`
`and alterations in drug dosage should take this
`
`delayed effect into account. Moreover, the increase
`
`in AUC with repeated dosage over several days may
`
`prove to have important toxicologic implications.
`
`This drug has several interesting facets.
`It has a
`
`prolonged effect on acid secretion that persists long
`after the drug has disappeared from plasma—pre-
`
`sumably because it accumulates in the parietal cell.
`
`This sustained action allows substantial control of
`
`
`
`gastric acidity with only once-daily dosage. To date
`
`omeprazole has been free of side effects which
`
`would be in keeping with it targeting to an enzyme
`
`specifically found so far only in parietal cells.
`It
`
`appears to also have the unusual property of improv—
`
`ing its own bioavailability with repeated dosage. It
`
`therefore seems likely that omeprazole, or related
`
`compounds, will be useful in a variety of conditions
`in which gastric acidity plays a pathogenetic role.
`i
`
`References
`
`1. Prichard PI, Yeomans ND, Mihaly GW, Iones DE. Smallwood
`RA. Louis W]. The effect of omeprazole an [H* + K*) ATPase
`inhibitor, on 24 h gastric pH profile in man. Aust NZ I Med
`1983;13:432—3.
`2. Lind T. Ccdcrberg C, Ekonvcd G, Haglund U. Olbe L. Effect of
`omeprazole—a gastric proton pump inhibitor—on pentagas-
`trin stimulated acid secretion in man. Gut 1983;24:270‘6.
`3. Fellenius E. Berglindh T. Sachs G. et a]. Substituted benz-
`imidazoles inhibit gastric acid secretion by blocking [H‘ +
`K‘] ATPase. Nature 1981;290:159—81.
`
`. Fellenius E, Elander B. Wallmark B. Helander H. Berglindh T.
`Inhibition of acid secretion in isolated glands by substituted
`benzimidazoles. Am I Physio] 1982;243:C505—10.
`. Wallmark B, Iaresten ELM, Larsson H. Ryberg B, Brandstrom
`A, Fellenius E. Differentiation among inhibitory actions of
`omeprazole, cimetidine, and SCN’ on gastric acid secretion.
`Am I Physio] 1983;245:664—71.
`Saccomani G, Helander HF, Crago S. Chang HH, Dailey DW.
`Sachs G. Characterization of gastric mucosa] membranes. X.
`Immunological studies of gastric [H‘ + K’t A’I‘Pase.
`I Cell
`Bio]1979;83:271—83.
`. Forte IF. Lee HC. Gastric adenosine triphosphatases: a review
`of their possible role in NC] secretion. Gastroenterology 1977,
`73:92176.
`. Gustavsson S, Adami H. Leaf L, Nyberg A. Nyrén 0. Rapid
`healing of duodenal ulcers with omeprazole. double-blind
`dose-comparative trial. Lancet 1983:ii:124w5.
`. Walan A, Bergsaker-Aspoy I, Farup P, et a]. Four week study
`of the rate of duodenal ulcer healing with omeprazole [abstrI
`Gut 1983;24:A972.
`Blanchi A, Delchier I-C, Soule I-C, Payen D, Bader I-l’. Control
`of acute ZollingeriEllison syndrome with intravenous ome—
`prazole. Lancet 1982:ii;1223—4.
`(jberg K. Lindstrom K. Reduction of gastric hypersecretion in
`Zollinger—Ellison syndrome with omeprazole. Lancet 1983;
`i266—7.
`Iansen IBMI, Olbe L.
`Lamers CBHW, Lind T, Moberg S.
`Omeprazole in Zollinger—Ellison syndrome. New Engl I Med
`1984;310:758—61.
`Walt RP, Gomes M de FA. Wood EC. Logan LH, Founder RE.
`Effect of daily oral omeprazole on 24 hour intragastric acidity.
`Br Med] 1983;287:12—4.
`Londong W, Londong V, Cederberg C, Steffen H. Dose—re-
`sponse study of omeprazole on meal-stimulated gastric acid
`secretion and gastrin release. Gastroenterology 1983;135:1373—
`8.
`Mihaly CW, Prichard PI. Smallwood RA. Yeomans ND. Louis
`WI. Simultaneous high pressure liquid chromatographic anal-
`ysis of omcprazole and its sulphone and sulphide metabolites
`in human plasma and urine. I Chromatogr 1983;278:3114].
`Gibaldi M. Perrier D. Pharmacokinetics. 2nd ed. New York:
`Marcel Dekker. 1982.
`Soka] RR, Rohlf FI. Biometry. 2nd ed. San Francisco: WH.
`Freeman. 1981.
`Elashoff JD. Down with multiple t-tests. Gastroenterology
`1981;80:615—20.
`Walt RP. Male Ill, Rawlings I, Hunt RH, Milton-Thompson
`GI, Misiewicz II. Comparison of
`the effects of ranitidine.
`cimetidine and placebo on the 24 hour intragastric acidity
`and nocturnal acid secretion in patients with duodenal ulcer.
`Gut 1981;22:49—54.
`Pounder RE, Williams IG. Milton-Thompson GI, Misiewicz I].
`Effect of cimetidine on 24-hour intragastric acidity in normal
`subjects. Gut 1976;17:133—8.
`Peterson WL. Barnett C, Feldman M, Richardson CT. Reduc»
`tion of twenty-four-liour gastric acidity with combination
`drug therapy in patients with duodenal ulcer. Gastroenterol-
`ogy 1979;77:1015720.
`Lucas M. pH or hydrogendon concentration in statistic.
`Lancet 1977:ii:826.
`Muller P, Dammann H-G, Seitz H, Simon B. Effect of repeated
`once~dai]y. ora] omeprazole on gastric secretion. Lancet 1983;
`i:66.
`Larsson H, Carlsson E, Iunggren V, et al. Inhibition of gastric
`acid secretion by omeprazole in the dog and rat. Gastroenter-
`ology 1983;85:90077.
`
`20.
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`21.
`
`22.
`
`23.
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`24.
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`10.
`
`11.
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`12.
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`13.
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`14.
`
`15.
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`16.
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`17.
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`18.
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`19.
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`Page 6
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`Dr. Reddy's EXh. 1056
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`Page 6
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`Dr. Reddy's Exh. 1056
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