Aliment Pharmacol Ther 2004; 20: 399–406.
`
`doi: 10.1111/j.1365-2036.2004.02079.x
`
`Intragastric acid suppression and pharmacokinetics of twice-daily
`esomeprazole: a randomized, three-way crossover study
`
`P. O. KAT Z*, D. O. CA STELL , Y. CHENà, T. AND ERSS ONà & M. B. SOSTEKà
`*Division of Gastroenterology and Nutrition, Albert Einstein Medical Center, Philadelphia, PA;  Department of
`Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC; àClinical Science, AstraZeneca LP,
`Wilmington, DE, USA
`
`Accepted for publication 21 May 2004
`
`SUMMARY
`
`Background: Patients with refractory gastro-oesophageal
`reflux disease, extra-oesophageal
`reflux symptoms,
`Barrett’s oesophagus, or Zollinger–Ellison syndrome
`may require greater acid suppression than that obtained
`with once-daily esomeprazole.
`Aim: To assess gastric acid suppression (determined by
`intragastric pH) and pharmacokinetics of twice-daily vs.
`once-daily esomeprazole.
`three-way
`Methods:
`In a randomized, double-blind,
`crossover study, healthy subjects received esomeprazole
`40 mg once daily, 20 mg twice daily, or 40 mg twice
`daily for five consecutive days. Twenty-four-hour con-
`tinuous ambulatory intragastric pH was recorded on day 5.
`
`Results: Esomeprazole 40 mg twice daily provided a
`mean of 19.2 h with intragastric pH > 4.0 (80.1% of a
`24-h time period; 95% confidence interval 74.5–85.7%)
`vs. 14.2 h with 40 mg once daily (59.2%; 95% CI
`53.7–64.7%) and 17.5 h with 20 mg twice daily
`(73.0%; 95% confidence interval 67.4–78.5%) in 25
`subjects. Intragastric pH was maintained >4.0 for a
`similar percentage of time during active and sleeping
`periods for all doses.
`Conclusions: Esomeprazole 40 mg twice daily provides
`significantly greater acid suppression (number of hours
`in a 24-h period with pH > 4.0) than once-daily dosing
`and may be a reasonable consideration for patients
`requiring greater acid suppression for acid-related
`disease.
`
`INTRODUCTION
`
`Prolonged suppression of gastric acid secretion is
`important for the effective pharmacologic management
`of acid-related disease. Indeed, the healing of erosive
`oesophagitis secondary to gastro-oesophageal reflux is
`directly related to the percentage of time during a 24-h
`period that
`intragastric pH is maintained above a
`threshold of 4.0.1 Highly effective intragastric acid
`suppression is particularly important for patients with
`refractory gastro-oesophageal reflux disease (GERD),
`
`Correspondence to: Dr P. O. Katz, Klein Building, Suite 331, 5501 Old
`York Road, Philadelphia, PA 19141, USA.
`E-mail: pkatz19512@aol.com
`
`extra-oesophageal reflux symptoms, Barrett’s oesopha-
`gus, or Zollinger–Ellison syndrome who may require
`twice-daily dosing with a proton pump inhibitor (PPI)
`for satisfactory clinical management.2
`Proton pump inhibitors provide the most effective and
`durable gastric acid suppression relative to other
`classes of drugs used for the treatment of acid-related
`disease. Esomeprazole is the most recent PPI to become
`available for clinical use, and its acid-suppressive
`pharmacodynamics have been well
`characterized.
`Esomeprazole 40 mg once daily provided greater
`control of
`intragastric pH, as determined by the
`percentage of a 24-h period with pH > 4.0,
`than
`standard oral doses of all other available PPIs at steady
`state.3–6
`
`Ó 2004 Blackwell Publishing Ltd
`
`399
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`

`400
`
`P. O. KATZ et al.
`
`Observational studies have shown that esomeprazole
`40 mg twice daily is effective for the treatment of acid-
`related disease among patients who do not respond
`completely to once-daily treatment.7 However,
`the
`pharmacodynamic and pharmacokinetic
`effects of
`twice-daily esomeprazole have not been evaluated
`systematically. The aim of this study was to assess the
`24-h intragastric pH and pharmacokinetic profile of
`esomeprazole 40 mg twice daily, 20 mg twice daily and
`40 mg once daily at steady state. In addition, the
`intragastric pH profile during active and sleeping
`periods was evaluated with each of these three dosing
`regimens.
`
`MATERIALS AND METHODS
`
`Subjects
`
`Healthy men and women between 18 and 50 years of
`age, recruited from the general population by local
`advertisements, were eligible for inclusion into this
`study (AZ GI Protocol 277). Eligible subjects were
`considered healthy based on a detailed medical history,
`physical examination, and clinical laboratory evalua-
`tion. Subjects were excluded if they had a medical
`condition, including gastrointestinal disease, that could
`affect the pharmacokinetics or absorption of esomep-
`razole or if they had a known intolerance to other
`currently approved PPIs or any ingredient in their
`formulation. Pregnant or lactating women, and those of
`childbearing potential who were deemed to be using
`inadequate contraceptive measures were also excluded.
`Volunteers with drug allergies or a history of drug or
`alcohol abuse, smokers or consumers of nicotine-
`containing products within 3 months prior to the first
`dose of esomeprazole or during the study, consumers of
`more than four cups of caffeine-containing beverages
`per day, and those with a significant clinical
`illness
`within 2 weeks prior to the first dose of esomeprazole or
`during the study were also prohibited from entry into
`the trial. Helicobacter pylori serology (Flexsure; Beckman
`Coulter, Brea, CA, USA) and CYP2C19 genotyping were
`performed on all subjects at the screening visit, but the
`results did not influence entry into the study [a mutated
`or defective CYP2C19 gene is predictive of a subject
`being a ‘poor metabolizer’, which could result in higher
`values for the area under the plasma concentration–
`time curve (AUC(0-24h)) for esomeprazole than those of
`the general population].
`
`Study design and procedures
`
`In this randomized, double-blind, multiple-dose, three-
`way crossover study, each dosing sequence comprised
`three 5-day dosing periods separated by a washout
`interval of 10–17 days. The study was cyclically
`designed to assure that pH studies were performed on
`the same day each week. Thus, the duration of the
`study for each participant ranged between 5 and
`7 weeks, depending on the length of each washout
`period.
`The three dosing regimens of esomeprazole (Nexium;
`AstraZeneca LP, Wilmington, DE, USA) were 40 mg
`once daily in the morning plus matched placebo in the
`afternoon to maintain blinding, 40 mg twice daily and
`20 mg twice daily. The 20 mg and 40 mg doses of
`esomeprazole looked identical to preserve the integrity
`of blinding. Participants were randomized into one of
`six possible dosing sequences in a 1:1:1:1:1:1 ratio
`using a computer-generated schedule. Eligible subjects
`at each of the two study centres (Graduate Hospital,
`Philadelphia, PA, USA and MDS Pharma Services,
`Neptune, NJ, USA) were given the next sequential
`enrolment number and the next sequential allocation
`number based on preprinted numbers on study drug
`labels.
`The subjects visited the study centre twice daily to
`receive study medication and standardized meals
`(breakfast and dinner). Study medication was given
`with 200 mL of water 30 min before each meal, at
`8.00 am and 6.00 or 8.00 pm.
`On day 5 of each dosing period, the subjects reported to
`the study centre for study drug administration, 30 min
`prior
`to breakfast, and remained there until
`the
`morning of day 6 when the 24-h pH monitoring and
`pharmacokinetic sampling procedures were completed.
`Subjects were not permitted to lie down during upright
`(active) periods of
`testing. The supine period was
`restricted to night-time hours to reflect typical sleeping
`hours.
`
`Measurement of intragastric pH
`
`Twenty-four-hour continuous intragastric ambulatory
`pH was recorded for each subject on day 5 of each of the
`three dosing periods. A microelectrode was inserted
`when the subject arrived at the investigational site at
`7:30 am, prior to breakfast and administration of study
`medication, and was removed the following morning
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 399–406
`
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`TWICE-DAILY ESOMEPRAZOLE: GASTRIC ACID CONTROL AND PHARMACOKINETICS
`
`401
`
`before 8.00 am; meal time recordings were excluded
`from all pH calculations. During the first pH recording,
`the electrode was placed 10 cm distal to the lower
`oesophageal sphincter (as determined by manometry)
`and the distance from the nares recorded for use in
`placing the electrode during all subsequent pH record-
`ings. The electrode was calibrated before and after each
`24-h recording. The microelectrode measured the
`difference in potential between the recording and
`reference electrodes in the tip of the probe and, every
`4 s, calculated a median value that was converted into
`pH and recorded on the attached Medtronics gastro-
`graph data logger (Minneapolis, MN, USA). The amount
`of time in hours that the subjects were supine (sleeping)
`was recorded.
`The data presented here are the number of hours of a
`24-h period that intragastric pH exceeded a pH of 4.0
`during steady state. Also presented is the evaluation of
`the amount of time within a 24-h period that intragas-
`tric pH exceeded 4.0 during supine (sleeping) and
`upright
`(active) periods at steady state by dosing
`regimen. The number of hours that intragastric pH
`exceeded values of 3.0, 3.5, 4.5, 5.0, 5.5 and 6 was also
`assessed.
`
`Pharmacokinetics
`
`Venous blood samples were collected for the determin-
`ation of
`esomeprazole plasma concentrations at
`25 predefined time points during the 24-h period on
`day 5 of each dosing period. The plasma concentrations
`of esomeprazole were determined at MDS Pharma
`Services Analytical Laboratories (Lincoln, NE, USA)
`using liquid chromatography with MS/MS detection
`with a limit of quantitation of 5.0 ng/mL.
`The primary pharmacokinetic parameters, peak con-
`centration (Cmax) and AUC(0-24h), were calculated at
`steady state for each subject and summarized for each
`dosing regimen. In addition, the time to peak concen-
`tration (Tmax),
`terminal plasma elimination half-
`life (t1/2) and the terminal elimination rate constant kz were
`determined using standard pharmacokinetic formulas.
`
`Safety and tolerability
`
`All randomized subjects who received at least one dose
`of esomeprazole were included in the population
`evaluated for safety. Clinical
`laboratory evaluations
`(serum chemistry, haematology and urinalysis) were
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 399–406
`
`completed prior to and at the end of each dosing period.
`Adverse events and vital signs (blood pressure, pulse
`rate and respiratory rate) were evaluated at each visit.
`The possible relationship with study drug and severity
`(mild, moderate or severe) of each adverse event were
`rated by the investigator. In addition, body weight was
`measured and an electrocardiogram (ECG) was recorded
`at the screening visit and at the end of each dosing
`period.
`
`Statistical analysis
`
`It was expected that 24 subjects would need to be
`enrolled to provide sufficient evaluable intragastric pH
`and pharmacokinetic data to enable selection of an
`optimal dosing regimen from the three esomeprazole
`regimens that were evaluated. All pH traces and
`pharmacokinetic data were manually reviewed by a
`single investigator blinded to subject, treatment, and
`treatment period, to determine the evaluability of data.
`Any obviously invalid recordings were excluded from
`the analysis.
`The pharmacodynamic and pharmacokinetic parame-
`ters, log transformed AUC(0-24h) and Cmax, were ana-
`lysed using an analysis of variance model with effects
`for sequence, subject (sequence), period, and dosing
`regimen. AUC(0-24h) and pH were correlated using
`scatterplots to evaluate the relationship between pH
`data and pharmacokinetic parameters. The least-square
`means and 95% confidence intervals (CIs) were calcu-
`lated for the primary and secondary pharmacodynamics
`end points for each dosing regimen. All analyses were
`performed using the statistical software package SAS,
`Version 6.12 (SAS Institute, Cary, NC, USA).
`
`Ethics
`
`This study was conducted in accordance with the
`Declaration of Helsinki, Food and Drug Administration
`guidance, Good Clinical Practice regulations, and
`Guidelines for the Monitoring of Clinical Investigations.
`In addition, local Institutional Review Board approval
`was obtained and each subject provided written
`informed consent prior to enrolment.
`
`RESULTS
`
`Twenty-nine subjects (20 males and nine females) were
`randomized and each received at least one dose of
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`

`402
`
`P. O. KATZ et al.
`
`Esomeprazole dosing
`regimen
`
`% of full 24-h period
`LSM (95% CI)
`
`% of upright period
`LSM (95% CI)
`
`% of supine period
`LSM (95% CI)
`
`40 mg once daily
`20 mg twice daily
`40 mg twice daily
`
`59.2 (53.7–64.7)
`73.0 (67.4–78.5)*
`80.1 (74.5–85.7)*
`
`57.9 (49.0–66.9)
`58.6 (51.9–65.3)
`70.0 (63.5–76.6) 
`79.2 (70.5–87.9)*
`81.0 (74.4–87.6)*à 83.7 (74.9–92.4)*
`
`Table 1. Percentage of time with intragas-
`tric pH > 4.0 on day 5 of esomeprazole
`dosing in evaluable subjects (n ¼ 25)
`
`*
`
`17.5
`
`*
`
`19.2
`
`14.2
`
`40 mg
`once daily
`
`20 mg
`twice daily
`
`40 mg
`twice daily
`
`20
`
`16
`
`12
`
`048
`
`periodpH>4.0
`
`Mean number of hours in a 24-h
`
`Figure 1. Mean number of hours with intragastric pH > 4.0 on
`day 5 of esomeprazole dosing in evaluable subjects (n ¼ 25).
`*P < 0.001 vs. 40 mg once daily.
`
`three dosing regimens, an intragastric pH > 4.0 was
`observed for more than 14 h of
`the 24-h period
`(Figure 1). With esomeprazole 40 mg twice daily,
`intragastric pH was >4.0 for >19 h of the 24-h testing
`period. When the three dosing regimens were com-
`pared statistically, the differences in percentage of time
`with pH > 4.0 were significant in all six pair-wise
`comparisons that evaluated twice-daily vs. once-daily
`dosing (P £ 0.02).
`Within each dosing regimen, esomeprazole main-
`tained a pH > 4.0 for a similar percentage of time
`regardless of whether subjects were sleeping or active.
`Esomeprazole 40 mg twice daily provided an intragas-
`tric pH > 4.0 for more than 80% of the time during
`both sleeping and active periods. The mean number of
`hours that subjects were asleep (supine) was 7.7 h (s.d.
`0.8 h) with 40 mg once daily, 7.8 h (s.d. 1.0 h) with
`20 mg twice daily and 7.8 h (s.d. 0.8 h) with 40 mg
`twice daily.
`The per cent of the sleep and active periods that pH
`remained above pH 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 and 6.0
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 399–406
`
`* P < 0.001 vs. esomeprazole 40 mg once daily.
`  P ¼ 0.02 vs. esomeprazole 40 mg once daily
`à P ¼ 0.02 vs. esomeprazole 20 mg twice daily.
`CI, confidence interval; LSM, least-squares mean.
`
`esomeprazole. During the study, one subject was lost to
`follow-up, one subject withdrew consent, and the
`sponsor and investigator withdrew one subject due to
`a positive drug screen. The number of subjects who
`completed esomeprazole 40 mg once daily, 40 mg twice
`daily and 20 mg twice daily dosing periods were 26, 28
`and 27, respectively. Data from one subject were not
`evaluable due to elevated baseline values of alanine
`aminotransferase and aspartate aminotransferase con-
`sistent with active hepatitis, representing a major
`violation of enrolment criteria.
`In total, 25 subjects completed all three dosing periods
`and comprised the evaluable cohort. Of the evaluable
`population (n ¼ 25, 18 men and seven women), the
`mean (s.d.) age was 36.8 (8.1) years. Seven were white,
`15 were African–American, and three represented other
`ethnicities. Five (20%) of the subjects were H. pylori
`seropositive. One subject was homozygous for CYP2C19
`polymorphism (considered a ‘poor metabolizer’) but was
`included in the evaluable population. In the remaining
`24 subjects, CYP2C19 genotype polymorphism was not
`detected (predictive of an ‘extensive metabolizer’). The
`washout period ranged from 10 to 18 days.
`
`Intragastric pH
`
`The mean number of hours of pH data available was
`23.43 for the esomeprazole 40 mg once daily group,
`24.00 for the esomeprazole 40 mg twice-daily group
`and 23.97 for the esomeprazole 20 mg twice-daily
`group.
`The percentage of time of a 24-h period that pH
`remained >4.0 was
`significantly higher with the
`esomeprazole twice-daily dosing regimens compared
`with the esomeprazole 40 mg once-daily regimen
`during the 24-h monitoring period, and during the
`supine (sleeping) portion and the upright
`(active)
`portion of the monitoring period (Table 1). For all
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`TWICE-DAILY ESOMEPRAZOLE: GASTRIC ACID CONTROL AND PHARMACOKINETICS
`
`403
`
`with the three dosing regimens of esomeprazole is
`shown in Figure 2. Esomeprazole maintained intragas-
`tric pH above these pH thresholds
`for a similar
`proportion of the sleeping and active periods regardless
`of the dosing regimen.
`
`Pharmacokinetics
`
`The evaluable population for the pharmacokinetic
`calculations included 25 subjects, with the exception
`of AUC(0-24h) for the esomeprazole 20 mg twice-daily
`dose regimen, for which the evaluable population was
`
`Night
`Day
`
`>3.0
`
`>3.5
`
`>4.0
`
`>4.5
`
`>5.0
`
`>5.5
`
`>6.0
`
`pH threshold
`
`24 subjects. One patient from the 20 mg twice-daily
`group was excluded because AUC(0-24h)could not be
`calculated for that dosing period.
`Pharmacokinetic parameters for all dosing regimens
`are provided in Table 2. Both Tmax and t1/2were similar
`across the three dosing regimens, at approximately 1.1
`and 1.5 h, respectively. For AUC(0-24h), the esomepraz-
`ole 40 mg twice-daily dosing regimen produced values
`more than twofold higher than that of the 40 mg
`once-daily and 20 mg twice-daily regimens. For Cmax,
`the esomeprazole 40 mg twice-daily dosing regimen
`produced values higher than that of the 40 mg once-
`daily and 20 mg twice-daily regimens. When the three
`dosing regimens were
`compared statistically,
`the
`differences in AUC(0-24h) were significant in two of
`the three pair-wise comparisons (esomeprazole 40 mg
`twice daily vs. 20 mg twice daily and 40 mg once
`daily, P < 0.0001), and the differences in Cmax were
`significant
`in
`all
`three
`pair-wise
`comparisons
`(P £ 0.05).
`Across the three dosing regimens, there was a poor
`correlation between the per cent of time that intragas-
`tric pH > 4 and AUC (Figure 3).
`
`(a)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`%ofperiod
`
`(b)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`%ofperiod
`
`(c)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`%ofperiod
`
`Night
`Day
`
`Safety and tolerability
`
`>3.0
`
`>3.5
`
`>4.0
`
`>4.5
`
`>5.0
`
`>5.5
`
`>6.0
`
`pH threshold
`
`Night
`Day
`
`Esomeprazole was well tolerated and there were no
`serious adverse events or discontinuations because of
`an adverse event. The number of subjects reporting
`any adverse event (adverse event considered related to
`study drug) was 7 (3) of 26 subjects with esomeprazole
`40 mg once daily, 4 (1) of 27 with esomeprazole
`20 mg twice daily, and 6 (0) of 29 with esomepraz-
`ole 40 mg twice daily, respectively. All adverse events
`have been previously observed,8 and the most fre-
`quently reported were headache (four subjects), nausea
`(three subjects), vomiting (three subjects) and diar-
`rhoea (two subjects). ECG data demonstrated no sign of
`QT prolongation or any other clinically meaningful
`changes between baseline and the end of each dosing
`period for all regimens.
`
`>3.0
`
`>3.5
`
`>4.0
`
`>4.5
`
`>5.0
`
`>5.5
`
`>6.0
`
`pH threshold
`
`DISCUSSION
`
`Figure 2. Least-square mean per cent of time during sleep and
`active periods that intragastric pH was maintained above pH
`thresholds with esomeprazole 40 mg twice daily (a), 40 mg once
`daily (b), and 20 mg twice daily (c). Bars depict 95% confidence
`intervals.
`
`This crossover study demonstrated that esomeprazole
`40 mg twice daily provided a significantly longer
`duration of gastric acid suppression as measured by
`intragastric pH, and a significantly higher AUC(0-24h)
`and Cmax at steady state as compared with esomeprazole
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 399–406
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`

`404
`
`P. O. KATZ et al.
`
`Table 2. Pharmacokinetics of esomeprazole at steady-state*
`
`AUC(0-24h) (lmolÆh/L)
`
`Cmax (lmol/L)
`
`Tmax (h)
`
`t1/2 (h)
`
`Esomeprazole dosing regimen
`
`LSM (95% CI)
`
`LSM (95% CI)
`
`Median (range)
`
`Mean (s.d.)
`
`40 mg once daily
`3.46 (2.90–4.11)
`1.25 (0.75–8.00)
`1.45 (0.43)
`9.52 (8.87–10.23)
`2.18 (1.83–2.60)à
`20 mg twice daily
`1.00 (0.75–3.97)
`1.40 (0.54)
`9.33 (8.67–10.04)
`22.01 (20.47–23.66) 
`40 mg twice daily
`4.48 (3.75–5.34)§
`1.17 (0.75–4.00)
`1.48 (0.39)
`* All values based on the evaluable subject population (n ¼ 25). One subject was excluded from the 20 mg twice-daily group for AUC(0-24h)
`because of incomplete data.
`  P < 0.0001 vs. esomeprazole 20 mg twice daily and esomeprazole 40 mg once daily.
`à P ¼ 0.003 vs. esomeprazole 40 mg once daily.
`§ P < 0.0001 vs. esomeprazole 20 mg twice daily and P < 0.05 vs. esomeprazole 40 mg once daily.
`LSM, least-squares mean; s.d., standard deviation; CI, confidence interval.
`
`40 mg QAM
`
`20 mg BID
`
`40 mg BID
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`AUC(0–24h)
`
`Figure 3. Relationship between pH > 4.0
`and area under the curve by dose regimen
`[excluding Helicobacter pylori-seropositive
`subjects and poor metabolizer (subject
`homozygous for CYP2C19 polymorphism)].
`
`110
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`PercenttimepH>4.0
`
`40 mg once daily. The lower dose of esomeprazole
`20 mg twice daily also provided a significantly longer
`duration of gastric acid suppression than esomeprazole
`40 mg once daily, but was not as effective for gastric
`acid suppression as esomeprazole 40 mg twice daily.
`Moreover, in our study, the correlation between intra-
`gastric pH and AUC was poor, and AUC appears to be a
`poor predictor of pharmacodynamic effect. In contrast,
`previous analyses have shown a direct correlation
`between acid control and AUC with esomeprazole
`40 mg once daily (at a fixed Cmax).9 This apparent
`discrepancy may be explained by a prolongation of
`the period of time with effective plasma drug concen-
`trations as a result of twice-daily dosing. An observation
`of a similar effect in the previous analyses may support
`
`this hypothesis; although AUC was decreased by food
`intake, the per cent of time with pH > 4 was not
`appreciably altered, which was attributed to just such
`an extended period of time with quantifiable plasma
`concentrations.9 This may explain why in the current
`study, the per cent of time with pH > 4 was greater
`with esomeprazole 20 mg twice daily vs. 40 mg once
`daily, although the AUC values for these treatments
`were similar.
`Other investigators have reported the pharmacody-
`namic effects of esomeprazole once daily at steady state
`and our results largely concur with their findings. Miner
`et al. observed intragastric pH > 4.0 for 58.3% of a 24-h
`period with esomeprazole 40 mg once daily in patients
`with GERD in a study conducted in the United States;4
`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 399–406
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`TWICE-DAILY ESOMEPRAZOLE: GASTRIC ACID CONTROL AND PHARMACOKINETICS
`
`405
`
`their results were in accordance with the 59.2% that we
`observed in our subjects.
`Effective resolution of acid-related symptoms and
`healing of oesophageal erosions can be achieved by
`inhibition of gastric acid secretion and reduction of
`oesophageal exposure to acid. The primary determinants
`of healing of erosive oesophagitis with acid-suppressing
`agents are the length of treatment, and the degree and
`duration of acid suppression during a 24-h period.1 In
`our study, esomeprazole provided effective intragastric
`acid suppression with once-daily and twice-daily dosing
`that was similar or greater than that reported with other
`PPIs.4, 10, 11 Twice-daily dosing of esomeprazole provi-
`ded superior control of pH compared with a double dose
`given once daily, as has been demonstrated with
`omeprazole.12, 13 In a five-way crossover comparative
`trial, esomeprazole produced an increased time with
`pH > 4.0 compared with all other available PPIs. This
`improved acid suppression with esomeprazole may
`provide an explanation for the improved efficacy of
`esomeprazole
`over
`omeprazole,
`lansoprazole
`and
`pantoprazole for symptom resolution, healing and/or
`maintenance of healing of erosive oesophagitis using
`recommended once-daily dosing schedules.14–18
`However, although more than 92% of patients achieve
`healing of erosive oesophagitis after 8 weeks of once-
`daily esomeprazole,14, 15, 17 twice-daily dosing may be
`required in certain circumstances. Comparative trials
`have not yet been published that directly compare the
`efficacy of once- vs. twice-daily dosing with esomepraz-
`ole. However, there is reason to consider that the greater
`acid inhibition achieved with double the standard dose
`of esomeprazole might provide complete healing, pre-
`vention of additional tissue injury, and assurance of
`optimal symptom relief in many patients refractory to
`once-daily treatment, and there is some evidence to
`suggest that this will be the case.1, 7 In one obser-
`vational study, esomeprazole 40 mg twice daily was
`recommended for patients with difficult-to-treat laryn-
`gopharyngeal reflux who had an incomplete response to
`treatment with esomeprazole 40 mg once daily.7 The
`majority of these patients achieved a positive clinical
`response following twice-daily dosing with esomepraz-
`ole. Their positive outcome may have been attributable
`to the pharmacodynamic and pharmacokinetic benefits
`of twice-daily compared with once-daily esomeprazole.
`In conclusion, esomeprazole 40 mg twice daily pro-
`vides more hours of gastric acid control with pH > 4.0
`than once-daily dosing with 40 mg within a 24-h
`
`period, and its effectiveness is equally well maintained
`during active and sleeping periods. For patients with
`more severe manifestations of GERD who require
`greater acid suppression for adequate therapeutic
`management, esomeprazole 40 mg twice daily appears
`to be a rational therapeutic option.
`
`ACKNOWLEDGEMENTS
`
`for this study was provided by
`Financial support
`AstraZeneca LP, Wilmington, DE, USA. The authors
`thank Magdy Shenouda for participation in the study
`and acknowledge the editorial assistance of Christopher
`Rains and Karen Van Hoeven.
`
`REFERENCES
`
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`2 DeVault KR, Castell DO. Updated guidelines for the diagnosis
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`1
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`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 399–406
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`18 Labenz J on behalf of the EXPO study group, Keeling NEklund
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`
`Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20, 399–406
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