Aliment Pharmacol Ther 2004; 19: 1105–1110.
`
`doi: 10.1111/j.1365-2036.2004.01949.x
`
`Effect of splitting the dose of esomeprazole on gastric acidity
`and nocturnal acid breakthrough
`
`J. HA MMER & B. SC HMIDT
`Universita¨tsklinik fu¨r Innere Medizin IV, Abteilung fu¨r Gastroenterologie und Hepatologie, Vienna, Austria
`
`Accepted for publication 12 March 2004
`
`SUMMARY
`
`Background: Twice-daily dosing is increasingly used to
`improve gastric acid control, although not all proton-
`pump inhibitors are more effective when doses are split.
`Standard dose esomeprazole provides better gastric acid
`control than other standard dose proton-pump inhibitors.
`Aims: To compare the effect of standard dose esomep-
`razole (1 · 40 mg) with 20 mg b.d. on gastric acidity.
`Methods: Thirteen healthy subjects participated in this
`crossover study, receiving esomeprazole 2 · 20 mg and
`1 · 40 mg for 7 days in random order with a washout
`period of at least 7 days. Gastric 24-h pH was measured
`on days 1, 2 and 6.
`
`Results: Median gastric 24-h pH was higher during 2
`· 20 mg esomeprazole on day 2 (P < 0.01), no
`differences were detected on day 6. Night-time gastric
`acid
`suppression was
`significantly
`improved
`by
`2 · 20 mg esomeprazole on all study days (P < 0.05).
`Nocturnal acid breakthrough was observed on all study
`days in subjects receiving 1 · 40 mg, but in only 85%
`(first night), 64% (second night), and 45% of subjects
`(sixth night) with 2 · 20 mg (P < 0.05).
`Conclusion: Splitting the esomeprazole dose improves
`initial acid suppression, this effect starts at the first
`night. Maximal benefit is achieved on day 2, while the
`effect on night-time acid control is detectable during the
`entire first week of treatment.
`
`INTRODUCTION
`
`The prevalence of abnormal oesophageal acid exposure
`of the oesophagus increases across the spectrum of
`gastro-oesophageal reflux disease (GERD), as one pro-
`gresses from non-erosive reflux disease through erosive
`oesophagitis to Barrett’s oesophagus.1 Therapy of acid-
`related disorders of the oesophagus aims to reduce acid
`load of the oesophagus by suppressing gastric acid
`production.2 Earlier generations of proton-pump inhib-
`itors (PPIs) in standard doses once daily have achieved
`80–85% symptom relief and healing in GERD, while
`newer agents achieve healing and symptom relief in
`even higher percentages, reaching up to 95%.3, 4
`However, while therapy of gastric acid-related disorders
`
`Correspondence to: Dr J. Hammer, Universita¨tsklinik fu¨r Innere Medizin IV,
`Wa¨hringer Gu¨rtel 18–20, 1090 Vienna, Austria.
`E-mail: johann.hammer@univie.ac.at
`
`has improved remarkably over the last decades, there
`are still patients and conditions that do not respond
`adequately to currently available therapy regimens.5, 6
`Healing of reflux oesophagitis and relief of symptoms is
`directly related to the percentage of time that the gastric
`pH is maintained above a pH of 4.0 over a 24 h
`period.7–9 Several regimens have been used to improve
`the degree of
`intragastric pH control,
`including pre-
`scription of an additional dose of histamine type 2
`receptor antagonists or splitting the dose of the PPI.
`The night-time interval may require special considera-
`tion.10 During the night period, patients with GERD and
`also healthy subjects continue to secrete acid and
`decrease the intragastric pH < 4 for at
`least 1
`continuous hour, even when taking PPI such as
`omeprazole or lansoprazole twice daily.11, 12
`The literature on the effect of splitting the PPI dose on
`gastric acidity is divergent for the different PPIs. Gastric
`acid control with omeprazole 40 mg once daily could be
`
`Ó 2004 Blackwell Publishing Ltd
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`1105
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`1106
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`J. HAMMER & B. SCHMIDT
`
`significantly improved when the dose was divided and
`taken before breakfast and dinner.11, 13 Lansoprazole,
`which has been proven to be similar effective as
`omeprazole when given once daily, has been less
`effective with split dosing when compared with omep-
`razole twice daily. Finally, splitting the dose of pantop-
`razole did not have any benefit on gastric acidity over a
`once daily regimen.14
`Recent
`studies have suggested that esomeprazole
`(ESO), the S-isomer of omeprazole,
`improves gastric
`acid control as well as healing of GERD compared with
`other PPIs that are currently available on the mar-
`ket.15–21 The pharmacological difference to the racemic
`mixture, omeprazole,
`is due to a decreased first-pass
`elimination and decreased systemic clearance that
`results in an increase of the area under the plasma
`concentration–time curve; this in turn is related to a
`prolonged availableness at the proton pump.22, 23 ESO
`is readily absorbed, the highest plasma concentration is
`being reached after approximately 1.5 h. Up to an
`ingested amount of 40 mg, plasma concentrations
`increase proportional to the ingested dose. Like all other
`PPIs,
`the antisecretory effect
`lasts longer than the
`plasma half-life. All PPI, including ESO, increase their
`inhibitory effect on the proton pump within the first
`treatment days until the effect reaches a plateau after
`1 week of treatment.22
`The effect of drugs on gastric acidity can be quantified
`by 24-h pH monitoring.
`In the present study, we
`hypothesized that the effect of once daily ESO on gastric
`acidity can be further improved by splitting the dose.
`We expected that especially night-time acid secretion
`would be affected by a twice daily regimen.
`
`METHODS
`
`Subjects
`
`Thirteen healthy volunteers (seven female, six male;
`mean age 30.6 years, range: 20–52 years) were recrui-
`ted by public advertisement. None had a history of
`gastrointestinal complaints and abdominal
`surgery
`(except appendectomy and cholecystectomy) and none
`used medication on a regular basis. Subjects were not
`allowed to use any medication during the study period.
`All subjects tested negative for Helicobacter pylori with
`the [13C] urea breath test. Subjects signed an informed
`consent for the protocol that was approved by the Ethics
`Committee of the University Hospital of Vienna, Austria.
`
`24-h pH monitoring
`
`A dual electrode antimony pH catheter (diameter
`2.1 mm), connected to a Flexilog 2000 ambulatory pH
`recorder (Oakfield Instrument, Ltd, Oxfordshire, England,
`Great Britain, UK), was used to continuously record pH
`values at 4-s intervals. The electrodes were calibrated
`prior to each recording as per the recommendations of the
`manufacturer in buffers of pH 1.1 and 7.0 at room tem-
`perature. The electrodes were positioned 15 cm apart on
`the tube. The tube was introduced into the subject’s
`stomach via the intranasal route. The position of the
`electrodes were obtained by determining the pH-step
`between the stomach and the oesophagus with the prox-
`imal electrode; thereafter, the tube was 5 cm withdrawn.
`Twenty-four hour ambulatory intragastric and distal
`oesophageal pH recording was performed after an
`overnight fast on days 1, 2 and 6 during both study
`series. Subjects were allowed to follow their daily
`routine. They were instructed to take the meals always
`at the same time during the study period with a similar
`composition and calorie content according to their
`individual preferences. The compositions of the meals
`were chosen individually by the study subjects.
`
`Study design
`
`Subjects were asked to participate in two series, receiving
`1 · 40 mg or 2 · 20 mg ESO, respectively, over a 7-day
`period with a washout phase between study series of at
`least 7 days and up to 3 weeks. The order of the two series
`was determined at random. Subjects were instructed to
`ingest the drugs with a small amount of water approxi-
`mately 15–30 min before breakfast (1 · 40 mg and first
`dose of 20 mg b.d.) and dinner (second dose of 20 mg
`b.d.). The first dose was given in the study centre after
`positioning of the pH-tube and was dissolved in 125 mL
`of water. As soon as the tube was in position, the
`pH-recording was started. The tube was left in position for
`48 h (days 1 and 2). At the end of day 2, the tube was
`gently removed. Subjects returned to the study centre on
`day 6, when the pH tube was repositioned for another
`24-h measurement.
`
`Data and statistical analysis
`
`Data collected from the Flexilog 2000 were downloaded
`onto an IBM-compatible computer that utilized Flexilog
`software (Oakfield Instrument, Ltd) to analyse the data.
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110
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`the
`From the oesophageal and gastric recordings,
`median pH and the percentage of time with a pH above
`4 were calculated for three time periods: the daytime
`interval (08:00–20:00 hours), the night-time interval
`(22:00–07:00 hours) and the full 24 h. Nocturnal acid
`breakthrough was defined as a trop in gastric pH under
`4 that lasted longer than 1 h.
`Gastric pH values were also converted to acid concen-
`trations and these concentrations were then plotted for
`the total 24 h period as well as for the day- and night-
`time intervals for each of the doses and study days.
`Integration of the area under the resulting curves (AUC)
`was performed using the trapezoid rule and provided an
`estimate of the 24-h intragastric acidity.
`Comparisons between study days were performed using
`Student’s t-test for paired observations. The proportion
`of subjects with nocturnal acid breakthrough was
`compared using McNemar’s test for paired proportions.
`A P-value of <0.05 was considered significant.
`
`RESULTS
`
`24 h Gastric acid control
`
`Compared with 1 · 40 mg ESO, 2 · 20 mg ESO
`increased the median gastric 24 h pH (P < 0.01) and
`percentage time with gastric pH > 4 (P < 0.05) on day 2
`and decreased gastric AUC of acidity on day 1 (P < 0.01)
`and day 2 (P < 0.01) (Table 1, Figure 1). No differences
`
`ESOMEPRAZOLE DOSE SPLITTING
`
`1107
`
`in acid suppression were detected on day 6 (P > 0.05).
`Gastric acid suppression with 2 · 20 mg ESO treatment
`was comparable on days 2 and 6 (P > 0.05).
`
`Day- and night-time gastric acid control
`
`During daytime hours, 2 · 20 mg ESO increased the
`median gastric pH (P < 0.05) and percentage time with
`gastric pH > 4 (P < 0.01) and decreased gastric AUC of
`acidity on day 2 (P < 0.05), but not on day 1 and day 6
`(P < 0.05) (Table 1).
`During night-time, gastric acid suppression was signi-
`ficantly improved by 2 · 20 mg ESO compared with
`1 · 40 mg on all study days (Table 1). Nocturnal acid
`breakthrough was observed in all subjects receiving
`1 · 40 mg on all study days. Each individual subject
`had between 1 and 3 episodes of nocturnal acid
`breakthrough (Figure 2a).
`During 2 · 20 mg ESO, nocturnal acid breakthrough
`was observed in only 85% (first night), 64% (second
`night), and 45% of subjects (sixth night) (P < 0.05 vs.
`1 · 40 mg ESO) (Table 1) During the sixth night, four
`subjects still had 1 episode of nocturnal acid break-
`through and two had 2 episodes (Figure 2b).
`
`Oesophageal acid control
`
`On all study days no differences in oesophageal acid
`parameters were found with the two different regimens
`
`Table 1. Parameters of gastric acidity in subjects treated with 1 · 40 and 2 · 20 mg esomeprazole on day 1, day 2 and day 6. Data are
`given as mean ± s.d.
`
`Day 1
`
`Day 2
`
`Day 6
`
`1 · 40 mg
`
`2 · 20 mg
`
`P-value 1 · 40 mg 2 · 20 mg P-value 1 · 40 mg 2 · 20 mg
`
`P-value
`
`24-h Values
`3.8 (0.5) N.S.
`3.4 (0.4)
`Median 24-h pH
`Percentage time pH > 4.0 36.0 (20.3) 44.4 (20.6) N.S.
`Area under curve
`2010 (909) 1405 (653) 0.01
`(AUC)-acidity
`Daytime values
`3.5 (0.7) N.S.
`4.0 (1.1)
`Median 24-h pH
`Percentage time pH > 4.0 50.1 (25.3) 36.9 (15.9) N.S.
`AUC-acidity
`633 (366)
`787 (246) N.S.
`Night-time values
`4.1 (1.1) 0.01
`3.0 (0.9)
`Median 24-h pH
`Percentage time pH > 4.0 29.7 (15.7) 46.3 (22.4) 0.05
`AUC-acidity
`981 (489)
`541 (298) 0.05
`Porportion with NAB (%)
`100
`85
`0.05
`
`NAB, nocturnal acid breakthrough.
`
`5.9 (0.6) 0.01
`4.9 (0.5)
`62.6 (15.2) 82.4 (13.6) 0.05
`999 (643) 350 (420) 0.01
`
`5.3 (0.4) N.S.
`5.0 (0.8)
`67.7 (19.6) 74.9 (18.3) N.S.
`753 (608) 534.5 (461) N.S.
`
`6.1 (0.7) 0.05
`5.6 (0.5)
`82.9 (10.1) 90.4 (7.6) 0.01
`232 (168)
`87 (66)
`0.05
`
`5.7 (0.5) N.S.
`5.4 (0.8)
`82.8 (17.7) 85.0 (11.4) N.S.
`193 (124)
`175 (160) N.S.
`
`5.4 (1.2) 0.01
`3.6 (1.1)
`42.5 (20.5) 72.8 (17.0) 0.01
`699 (378) 209 (171) 0.01
`100
`61
`0.05
`
`0.05
`5.1 (0.9)
`3.9 (1.3)
`48.9 (22.8) 68.1 (19.7) 0.05
`535 (290)
`279 (199) 0.05
`100
`46
`0.05
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110
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`acid breakthrough is present in a high proportion of
`healthy subjects at baseline and that a once daily dose of
`ESO could not eliminate this phenomenon. Splitting the
`dose had a significant effect on nocturnal acid control,
`and this effect increased from day 1 to day 6, the end of
`the study period.
`Acid-induced injury of the oesophagus depends on the
`pH of the refluxate and the healing rate of erosive
`oesophagitis by acid inhibitors is directly related to the
`duration of
`suppression of gastric acid secretion
`achieved over a 24-h period.7, 9 Several recent studies
`have demonstrated that ESO suppresses gastric acidity
`more potently than other PPIs.15, 16 Our data demon-
`strated that by splitting the daily dose, gastric acid
`control can further be improved. The maximal 24 h
`gastric acidity that has been achieved on day 6 during
`once daily dosing, has already been achieved on the
`second day during the b.d. regime.
`Splitting the dose of omeprazole has also been shown
`to provide superior
`intragastric pH control when
`compared with a double dose given once daily, whereas
`such a benefit has not been documented for other
`PPIs.11, 13, 14 The differences in PPI effect might be due
`to a variable reversibility of binding to the proton pump
`among the PPIs.24, 25 Proton-pump inhibition was
`generally thought
`to be irreversible, but
`this has
`recently been challenged. Binding of omeprazole for
`instance, seems to be reversed in vivo, while binding of
`pantoprazole to the proton pump seems to be truly
`irreversible,
`suggesting a longer duration of acid
`suppression with pantoprazole treatment; thus, the rate
`of recovery of the proton pump might be higher with
`omeprazole, leaving more proton pumps susceptible for
`another application 12 h after the morning dose. Thus,
`the reversibility of binding of omeprazole and ESO might
`be of some clinical benefit by allowing the option to split
`the dose whereby the effect on gastric acid suppression
`can be increased.
`significantly
`Oesophageal acid exposure was not
`different among the two ESO regimens in our study.
`It should be noted that subjects in this study did not
`have gastro-oesophageal reflux, thus intra-oesophageal
`pH measurement were not expected to be abnormal and
`in fact, there was very little nocturnal reflux in our
`study group. Future clinical studies have to demonstrate
`whether also oesophageal acid exposure in patients with
`gastro-oesophageal reflux disease can be reduced signi-
`ficantly by splitting the ESO dose. In the present study,
`we have evaluated the effect of splitting the ESO dose on
`
`1108
`
`J. HAMMER & B. SCHMIDT
`
`*
`
`1 x 40 mg
`2 x 20 mg
`
`24
`
`16
`
`8
`
`0
`
`Hours
`
`Day 1
`
`Day 2
`
`Day 6
`
`Figure 1. Time (h) per 24-h period with a pH above 4. Data
`are given as mean ± S.E.M., shaded area ¼ 1 · 40 mg
`esomeprazole, white area ¼ 2 · 20 mg esomeprazole. *P < 0.05
`vs. 1 · 40 mg esomeprazole.
`
`Three episodes
`Two episodes
`One episode
`
`Four episodes
`Two episodes
`One episode
`No episode
`
`1st night
`
`2nd night
`
`6th night
`
`1st night
`
`2nd night
`
`6th night
`
`(a)
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`% patients
`
`(b)
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`% patients
`
`Figure 2. Number of nocturnal acid breakthrough episodes
`during the 3 study days; (a) during 1 · 40 mg esomeprazole,
`(b) during 2 · 20 mg esomeprazole.
`
`of ESO. Median 24-h pH in the oesophagus remained at
`a level above 6.5 during all three measurement days
`and remained above 6.3 during the night-time periods,
`independent of the ESO regime.
`
`DISCUSSION
`
`The results of the present study demonstrate that gastric
`acid suppression with ESO,
`the most potent PPI
`currently on the market, can further be improved in
`the initial period of the treatment when the daily dose is
`divided into a morning and an evening dose. The
`beneficial effect was more pronounced during the night
`period and was detectable already in the first night of
`treatment. Our study has also confirmed that nocturnal
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110
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`

`gastric acid suppression during the initial week of
`treatment. It cannot be inferred from our data whether
`the effect of splitting the dose persists longer than the
`first week of treatment.
`A series of observations have demonstrated that an
`increase in nocturnal acid production occurs
`in
`subjects with GERD as well as in healthy subjects.10
`This also occurs in the presence of PPI therapy and it
`has been suggested that this so called nocturnal acid
`breakthrough might be responsible for nocturnal
`oesophageal acid exposure and persisting symptoms
`of GERD, although this concept has been questioned
`recently.26 Studies have suggested that addition of H2
`receptor antagonists at bedtime to an existing b.d. PPI
`regimen is more effective than PPI therapy alone in
`reducing nocturnal acid breakthrough.27 However,
`the effect of H2 receptor antagonists on nocturnal
`acid is only temporary and is not detectable after
`1 week of treatment.26, 28 In contrast, our findings
`suggest that splitting the ESO dose improves gastric
`night-time acid control and this effect
`increases
`during the first week. After 1 week of treatment, less
`than half of the subjects remained to have nocturnal
`acid breakthrough. The present study does not allow
`to conclude whether the proportion of subjects with
`nocturnal acid breakthrough would further decrease
`during longer ESO application with a split dose
`regime.
`It has to be pointed out that our study was conducted
`in healthy subjects, thus should be extrapolated with
`caution to patients with acid-related disorders. Our
`subjects were all tested H. pylori-negative. It has been
`shown that PPI therapy in H. pylori-negative healthy
`subjects is associated with a higher rate of nocturnal
`acid breakthrough compared with H. pylori-positive
`subjects,29 possibly because the presence of H. pylori
`infection leads to a more profound suppression of acid
`secretion during PPI treatment.30
`In conclusion, splitting the dose of ESO improves acid
`suppression in the first week of treatment. By twice daily
`dosing, maximal 24-h acid suppression is already
`achieved on the second day of treatment, while night-
`time acid control as well as acid breakthrough improved
`continuously within the first week of treatment by
`splitting the ESO dose.
`
`ACKNOWLEDGEMENT
`
`There was no financial support required for this study.
`
`ESOMEPRAZOLE DOSE SPLITTING
`
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`
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`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 1105–1110
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`MYLAN PHARMS. INC. EXHIBIT 1069 PAGE 6
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