Aliment Pharmacol Ther 2000; 14: 861–867.
`
`Esomeprazole provides improved acid control vs. omeprazole
`in patients with symptoms of gastro-oesophageal reflux disease
`
`T. LIND*, L. RYDBERG*, A . K YLEB A¨ CK*, A . JONSSON*, T. AN DERSSON(cid:160), G. HASSELGREN(cid:224),
`J. HOLMBERG(cid:224) & K. RO¨ HSS(cid:224)
`*Department of Surgery, Ka¨rnsjukhuset, Sko¨vde, Sweden; (cid:160)AstraZeneca LP, Wayne, PA, USA and (cid:224)AstraZeneca R&D,
`Mo¨lndal, Sweden
`
`Accepted for publication 27 April 2000
`
`SUMMARY
`
`Background: Esomeprazole (Nexium) is a new proton
`pump inhibitor
`for
`the treatment of acid-related
`diseases.
`study, 38
`Methods: In this double-blind crossover
`patients with gastro-oesophageal reflux disease (GERD)
`symptoms were randomized to esomeprazole 40 and
`20 mg and omeprazole 20 mg once daily for 5 days. On
`day 5 of each dosing period, 24-h intragastric pH and
`pharmacokinetic variables were measured.
`Results: Thirty-six patients aged 29–58 (mean 45)
`years completed the study. Esomeprazole 40 and
`20 mg maintained intragastric pH > 4 for (mean)
`16.8 and 12.7 h, respectively, vs. 10.5 h for omepra-
`
`zole 20 mg (P < 0.001 and P < 0.01). Twenty-four-
`hour median intragastric pH was significantly higher
`with esomeprazole 40 mg (4.9) and 20 mg (4.1) than
`with omeprazole 20 mg (3.6)
`(P < 0.001 and P <
`0.01). Area under the plasma concentration–time curve
`(AUC) was 80% higher for esomeprazole 20 mg vs.
`omeprazole, while that for esomeprazole 40 mg was
`more than five times higher (each P < 0.0001). Inter-
`patient variability in intragastric pH and AUC was less
`with esomeprazole than with omeprazole. Esomeprazole
`was well tolerated and there were no safety concerns.
`Conclusions: Esomeprazole provides more effective acid
`control
`than omeprazole, with reduced interpatient
`variability, thereby offering the potential for improved
`efficacy in acid-related diseases.
`
`INTRODUCTION
`
`It is well established that the aggressiveness of the
`gastric refluxate (as reflected in the degree of mucosal
`injury), along with the associated symptoms of gastro-
`oesophageal reflux disease (GERD), are highly pH
`dependent.
`In this
`regard, an intragastric acidity
`threshold of pH 4 serves
`to differentiate between
`aggressive and nonaggressive reflux, because a refluxate
`of pH < 4 not only contains active pepsin but also leads
`to more intense symptoms.1, 2 Strategies aimed at
`
`Correspondence to: Dr T. Lind, Department of Surgery, Ka¨rnsjukhuset,
`Sko¨vde, S-541 85, Sweden.
`E-mail: tore.lind@vgregion.se
`
`maintaining intragastric pH above this threshold rep-
`resent
`the key to effective management of GERD,
`because mucosal healing correlates directly with the
`proportion of the 24-h period with intragastric pH > 4.3
`This relationship explains why the effective, sustained
`acid control provided by proton pump inhibitors leads to
`prompt resolution of symptoms and high rates of
`oesophageal healing.4, 5 Proton pump inhibitors have
`therefore emerged as the initial treatment of choice for
`the management of GERD, as endorsed by the recent
`Genval Workshop Group.6
`Omeprazole, like other proton pump inhibitors, is a
`substituted benzimidazole that exists as a racemic
`mixture of
`the R- and S-isomers. Esomeprazole
`(Nexium; Astra Zeneca R&D, Sweden) is the S-isomer
`
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`862
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`
`of omeprazole and the first proton pump inhibitor to be
`developed as a single isomer for the treatment of
`acid-related diseases.
`In common with omeprazole,
`esomeprazole demonstrates highly effective inhibition
`of gastric acid secretion.7 Esomeprazole differs from
`omeprazole, however,
`in displaying lower first-pass
`hepatic metabolism and slower plasma clearance,
`resulting in higher plasma concentrations.8 The
`increased systemic bioavailability of esomeprazole offers
`the prospect of
`improved clinical efficacy and more
`effective management of acid-related diseases.
`The aim of
`this study was to compare the acid
`inhibitory effects, pharmacokinetics and safety of
`esomeprazole and omeprazole in patients with GERD.
`Comparisons were performed between the recom-
`mended dosage of omeprazole (20 mg once daily) and
`the corresponding dosage of esomeprazole; in addition
`the effects of a higher esomeprazole dosage (40 mg once
`daily) were investigated for evidence of a dose–response
`relationship.
`
`METHODS
`
`Patients
`
`Male and female patients with symptoms of suspected or
`confirmed (by investigation) GERD, aged 30–60 years,
`were eligible for inclusion. The main exclusion criteria
`were symptoms of gastrointestinal bleeding (e.g. mela-
`ena, haematemesis), any pharmacotherapy for GERD
`within the previous 2 weeks, and previous history of
`oesophago-gastric surgery. Patients with a history of
`alcoholism or drug abuse and those with significant
`concomitant diseases likely to interfere with the results
`of
`the study were also excluded from enrolment.
`Pregnant or nursing women, and those not likely to
`be using adequate contraceptive measures during the
`course of the study, were excluded. The study was
`performed according to the ethical principles of the
`Declaration of Helsinki, and the protocol was approved
`by the independent Ethics Committee of the University
`of Gothenburg, Sweden, prior to study commencement.
`Informed written consent was obtained from all
`patients.
`
`Study design
`
`The study used a double-blind, randomized, crossover
`design, comprising three 5-day dosing periods separated
`
`by washout intervals of at least 2 weeks. An initial
`screening visit comprised determination of patients’
`complete medical history, physical examination and
`measurement of laboratory safety variables, as well as a
`serological assessment of Helicobacter pylori status using
`routine methods. Eligible patients were randomized to
`receive oral therapy with esomeprazole 40 mg o.d.,
`esomeprazole 20 mg o.d. or omeprazole 20 mg o.d.
`Doses were to be administered at least 30 min before
`breakfast. In order to maintain patient and investigator
`blinding, all study medication was identical in appear-
`ance and comprised enteric-coated pellets within
`gelatine capsules. During the washout periods, patients
`were allowed to use antacids as needed for relief of reflux
`symptoms. Concomitant
`treatment with H2-receptor
`antagonists, prokinetic drugs or other proton pump
`inhibitors was not permitted during the study.
`
`Measurement of intragastric pH
`
`After an overnight fast, patients returned to the clinic
`on day 5 of each dosing period. Study medication was
`administered under the supervision of the investigator,
`after which 24-h intragastric pH was recorded using a
`microelectrode (Ingold bipolar glass; Mettler-Toledo
`GmbH, Switzerland) linked to a Digitrapper MK III
`recorder (Synectics AB, Sweden). The electrode was
`inserted transnasally and positioned about 10 cm below
`the lower oesophageal sphincter. Patients were mobile
`throughout the recording, and were instructed not to lie
`down for periods longer than 10 min during the day.
`Data were analysed using EsopHogram software
`(Synectics AB, Sweden) to calculate the percentage of
`the 24-h period for which intragastric pH exceeded 4,
`along with 24-h median intragastric pH. To ensure
`consistency of results, food and beverage intake was
`standardized throughout each day of intragastric pH
`measurement for all patients.
`
`Pharmacokinetics
`
`Venous blood samples were drawn at regular intervals
`up to 8 h after drug administration for pharmacokinetic
`determinations on day 5 of each dosing period. Plasma
`concentrations of esomeprazole and omeprazole were
`measured using normal-phase liquid chromatography
`and ultra-violet detection, as previously described.9 The
`following pharmacokinetic variables were determined:
`area under
`the plasma concentration–time curve
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`
`863
`
`(AUC); maximum plasma concentration (Cmax); terminal
`half-life (t(cid:137)kz); and time to Cmax (tmax). AUC was
`determined using the log-linear trapezoidal method
`(the residual area after the last data point was calcu-
`lated as Clast/kz, where Clast is the concentration at the
`last measurable data point and kz the terminal slope of
`the plasma concentration–time profile). t(cid:137)kz was calcu-
`lated as ln2/kz, while tmax was determined from the
`plasma concentration–time profile.
`
`Safety and tolerability
`
`All adverse events spontaneously reported, as well as
`those elicited by open questioning or observed by the
`investigator, were recorded. Routine laboratory safety
`variables,
`including blood and urine analysis, were
`assessed before and at the end of the study (2–5 days
`after completion of the last dosing period). Clinically
`significant
`changes
`in laboratory variables were
`followed up for as long as medically necessary.
`
`Statistical analysis
`
`Differences between treatment groups in 24-h median
`intragastric pH, the duration for which intragastric pH
`was > 4 and AUC were analysed using a mixed-model
`analysis of variance, with fixed effects for period, carry-
`over and treatment and a random effect for patients.
`Estimated means and treatment differences, together
`with 95% confidence intervals, were calculated. AUC
`values were log-transformed before the analysis. The
`results
`for AUC were then calculated by taking
`the exponential of the estimates, and are presented
`as geometric means together with 95% confidence
`intervals.
`
`RESULTS
`
`A total of 36 of 38 enrolled patients completed the
`study. One discontinuation was due to nonattendance,
`and another patient withdrew from the study as a result
`of an adverse event
`(tiredness) during a washout
`interval. Baseline demographic and clinical character-
`istics of the patients completing the study are shown in
`Table 1. All patients were Caucasian, and the majority
`(83%) were H. pylori-negative. About one-third of
`patients were smokers.
`Counting of returned study medication indicated 100%
`compliance during each active dosing period. No patient
`received concomitant medication during the study that
`was deemed likely to have affected the pharmacody-
`namic or pharmacokinetic findings.
`
`Intragastric pH
`
`The intragastric pH–time profiles following oral admin-
`istration of esomeprazole and omeprazole are shown in
`Figure 1. For both dosages of esomeprazole the percent-
`
`Table 1. Baseline demographics and clinical characteristics
`of evaluable patients (n = 36)
`
`Gender, male : female (%)
`Mean age, years (range)
`Mean bodyweight, kg (range)
`Positive H. pylori status (no. of patients)*
`Smokers (no. of patients)
`
`Duration of GERD (no. of patients)
`1–5 years
`> 5 years
`
`* As determined by serology.
`
`42 : 58
`45 (29–58)
`80 (46–108)
`6 (17%)
`13 (36%)
`
`9
`27
`
`Figure 1. Twenty-four-hour median
`intragastric pH–time profiles after 5 days’
`dosing with esomeprazole (40 and 20 mg
`once daily) and omeprazole (20 mg once
`daily) in 36 patients with symptoms of
`gastro-oesophageal reflux disease; arrows
`indicate timepoints at which standardized
`meals were served.
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`864
`
`T. LIND et al.
`
`Variable
`
`Mean duration (hours)
`with intragastric
`pH > 4 (95% CI)
`Mean percentage of 24-h
`period with intragastric
`pH > 4 (95% CI)
`24-h median intragastric
`pH (95% CI)
`
`Treatment group*
`
`Esomeprazole
`40 mg
`
`Esomeprazole
`20 mg
`
`Omeprazole
`20 mg
`
`16.8 (15.0–18.4)(cid:224) 12.7 (11.0–14.4)(cid:160) 10.5 (8.8–12.2)
`
`Table 2. Effect of 5 days’ dosing with
`esomeprazole or omeprazole on intragastric
`acidity in 36 patients with symptoms of
`gastro-oesophageal reflux disease
`
`69.8 (62.3–76.8)(cid:224) 53.0 (46.0–60.0)(cid:160) 43.7 (36.7–50.7)
`
`4.9 (4.5–5.2)(cid:224)
`
`4.1 (3.8–4.5)(cid:160)
`
`3.6 (3.2–3.9)
`
`* All doses given once daily.
`CI, confidence interval; (cid:160)P < 0.01 vs. omeprazole; (cid:224)P < 0.001 vs. omeprazole and esome-
`prazole 20 mg.
`
`the 24-h period for which intragastric pH
`age of
`remained > 4 was significantly higher compared with
`omeprazole (Table 2). Thus, esomeprazole 40 mg main-
`tained intragastric pH > 4 for about 6 h longer than
`omeprazole 20 mg (16.8 h vs. 10.5 h). This difference
`was about 2 h for esomeprazole 20 mg vs. omeprazole
`20 mg (12.7 vs. 10.5 h, respectively). As a result, mean
`24-h median intragastric pH was significantly higher
`for each dosage of esomeprazole compared with omep-
`razole. Furthermore, esomeprazole 40 mg was signifi-
`cantly more effective than the 20 mg dosage in terms of
`the pharmacodynamic response. The esomeprazole
`40 mg dosage also produced less interpatient variability
`(as expressed by standard deviation) in the percentage
`of time for which intragastric acidity exceeded pH 4
`(17.8%), compared with values of 19.7% and 22.8%,
`respectively, for esomeprazole 20 mg and omeprazole
`20 mg.
`
`In terms of individual patient responses, an intraga-
`stric pH > 4 was maintained for more than 12 h in
`92%, 54% and 44% of patients receiving esomeprazole
`40 mg, esomeprazole 20 mg and omeprazole 20 mg,
`respectively, and an intragastric pH > 4 was main-
`tained for more than 16 h in 56%, 24% and 14% of
`patients, respectively (Figure 2).
`A total of six patients were H. pylori-positive. In this
`patient sub-group there was no clinically relevant
`difference between the pharmacodynamic response to
`esomeprazole and omeprazole (data not shown).
`
`Pharmacokinetics
`
`Pharmacokinetic variables after 5 days’ dosing with
`esomeprazole or omeprazole are summarized in Table 3.
`AUC following dosing with esomeprazole 20 mg was
`approximately 80% higher than with omeprazole 20 mg;
`
`Figure 2. Percentage of patients main-
`taining intragastric pH > 4 for at least 8,
`12 and 16 h after 5 days’ dosing with
`esomeprazole (40 and 20 mg once daily)
`and omeprazole (20 mg once daily).
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`

`Table 3. Pharmacokinetic variables after
`5 days’ dosing with esomeprazole or ome-
`prazole in 36 patients with symptoms of
`gastro-oesophageal reflux disease
`
`PHARMACODYNAMICS/KINETICS OF ESOMEPRAZOLE
`
`865
`
`Treatment group*
`
`Variable
`
`Geometric mean AUC,
`lmol Æ h/L (95% CI)
`Median Cmax, lmol/L
`(range)
`Median t(cid:137)kz, h (range)
`Median tmax, h (range)
`
`Esomeprazole
`40 mg
`
`Esomeprazole
`20 mg
`
`Omeprazole
`20 mg
`
`12.64 (9.89–16.17)
`
`4.18 (3.27–5.35)
`
`2.34 (1.83–3.00)
`
`5.13 (1.59–9.61)
`
`2.42 (0.51–4.78)
`
`1.41 (0.15–3.51)
`
`1.6 (0.8–2.9)
`1.2 (1.0–4.0)
`
`1.3 (0.5–2.5)
`1.0 (0.5–8.0)
`
`1.0 (0.3–2.8)
`1.0 (0.5–6.0)
`
`* All doses given once daily.
`AUC, area under the plasma concentration–time curve; CI, confidence interval; Cmax, max-
`imum plasma concentration; t(cid:137)kz, terminal half-life; tmax, time to Cmax.
`
`for esomeprazole 40 mg, AUC was over five times higher
`vs. omeprazole. These differences were statistically sig-
`nificant
`(each P < 0.0001).
`Interpatient variability
`(standard deviation, based on log-transformed values)
`in AUC was less with esomeprazole 40 mg (0.47) and
`20 mg (0.64) than with omeprazole (0.73).
`Mean plasma concentration–time profiles for esomep-
`razole 40 and 20 mg and omeprazole are shown in
`Figure 3. Overall, Cmax values for each dosage of
`esomeprazole were higher than those observed for
`omeprazole (Figure 3 and Table 3), although tmax
`values were similar (median (cid:24)1 h) for all treatments.
`Plasma t(cid:137)kz values tended to be somewhat longer for
`esomeprazole (median 1.3 and 1.6 h) than for omep-
`razole (median 1.0 h) (Table 3).
`
`Safety and tolerability
`
`Both dosages of esomeprazole were well tolerated, and
`the profile and incidence of adverse events were similar
`
`Figure 3. Mean plasma concentration–time profiles after 5 days’
`dosing with esomeprazole (40 and 20 mg once daily) and
`omeprazole (20 mg once daily) in 36 patients with symptoms of
`gastro-oesophageal reflux disease.
`
`(cid:211) 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 861–867
`
`to that observed with omeprazole 20 mg. The most
`commonly reported adverse events were gastrointestinal
`complaints (e.g. abdominal pain, nausea, diarrhoea),
`respiratory infection and headache. Such adverse events
`were typically mild and did not necessitate drug
`discontinuation. No serious adverse events occurred
`during, or as a result of, treatment and there were
`no clinically relevant changes in laboratory safety
`variables.
`
`DISCUSSION
`
`Frequent and prolonged oesophageal exposure to gastric
`refluxate is pivotal to the pathogenesis of GERD. Indeed,
`the degree of mucosal injury,3 the frequency of reflux
`symptoms10 and the severity of oesophageal pain2 in
`GERD are functions of oesophageal acid exposure (i.e.
`duration of exposure and pH of the refluxate). Among
`the various intragrastric acidity thresholds that have
`been proposed to differentiate between aggressive and
`nonaggressive reflux, pH 4 appears optimal.1 Conse-
`quently, maintenance of an intragastric pH above 4 for
`the greater part of each 24-h period is crucial
`for
`ensuring oesophageal healing and symptom relief
`in
`GERD.
`Using this intragastric pH threshold, our findings show
`that esomeprazole achieves significantly greater acid
`control than omeprazole. Thus, esomeprazole increased
`the duration for which intragastric pH exceeded 4 and
`achieved a higher median intragastric pH across the
`entire 24-h period. These benefits were found with each
`dosage of esomeprazole (40 and 20 mg), although they
`were more pronounced with the 40 mg dosage. Indeed,
`the pharmacodynamic effect of esomeprazole 40 mg
`was significantly greater than that observed for the
`lower dosage. In view of this it would be pertinent to
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`866
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`T. LIND et al.
`
`assess the performance of esomeprazole 40 mg against
`omeprazole 40 mg. These findings can be explained by
`the increased AUC values for the higher dosage relative
`to both esomeprazole 20 mg and omeprazole (see
`Table 2). Potentially, higher AUC values for esome-
`prazole lead to increased delivery of the drug to the
`canalicular lumen of the parietal cell and hence more
`pronounced inhibition of acid secretion, in accordance
`with the association between the AUC value of
`omeprazole and its antisecretory effect.11 Coupled with
`reduced interpatient variability in pharmacodynamic
`response, these properties of esomeprazole may contri-
`bute towards improved clinical efficacy over omeprazole.
`Several studies have previously reported the effect of
`omeprazole on 24-h intragastric pH.3, 12, 13 At a dosage
`of 20 mg, for example, omeprazole raised intragastric
`pH to > 4 for about 60% of the 24-h interval in patients
`with GERD,3 whereas Blum and colleagues13 reported a
`mean value of 51% in healthy volunteers. Although
`the present study suggests a less pronounced acid
`suppressant effect for omeprazole 20 mg, this may be
`explained by different approaches to the way in which
`intragastric pH was measured and the disposition of
`food intake during the monitoring period. Indeed, a
`study in healthy volunteers found that omeprazole
`20 mg maintained intragastric pH > 4 for about
`40% of the 24-h interval,14 which is similar to the
`mean value reported in the present study (44%).
`Current H. pylori status may also have affected the
`results of such studies. In the present study, for example,
`intragastric pH tended to remain > pH 4 for a longer
`period of time for both esomeprazole and omeprazole
`among H. pylori-positive patients, although the small
`number of patients precluded a formal
`statistical
`analysis of such findings.
`As previously reported for omeprazole,15, 16 esomep-
`razole showed nonlinear pharmacokinetics. Thus, doub-
`ling the dosage of esomeprazole led to a 3-fold increase
`in AUC. In addition, the AUC of esomeprazole 20 mg
`was approaching double that of the same dosage of
`omeprazole. Although such findings are limited by the
`fact that we evaluated only two dosages of esomepraz-
`ole,
`the results suggest
`that
`the increased AUC of
`esomeprazole relative to omeprazole is attributable to
`differences in the rate of elimination. Such differences
`may explain the
`enhancement of acid control
`with esomeprazole compared with omeprazole, as
`previously
`discussed.
`Interestingly,
`esomeprazole
`showed less
`interpatient variability in AUC than
`
`this profile of esomeprazole
`omeprazole. Ultimately,
`may contribute to increased predictability of the ther-
`apeutic response in patients with acid-related disorders
`such as GERD.
`While we did not perform symptomatic assessments or
`endoscopic determinations of oesophageal healing in
`the present study, our preliminary findings for esomep-
`razole have potentially important implications for the
`treatment of patients with GERD. Indeed, patients with
`GERD can experience reflux of gastric contents into the
`oesophagus at any time, which underscores the need to
`provide
`sustained control of
`intragastric acidity
`throughout the 24-h period to alleviate symptoms.
`Using the threshold level of
`intragastric pH > 4,
`esomeprazole 40 mg achieved control of
`intragastric
`acidity for 70% of the 24-h period, compared with 44%
`for omeprazole 20 mg. Thus, the increased duration
`with intragastric pH > 4 observed during esomeprazole
`therapy may translate into improved symptom control
`in GERD and other acid-related diseases compared with
`omeprazole. In addition, enhanced acid control with
`esomeprazole has implications for the rate of oesopha-
`geal healing. Like symptoms,
`there is correlation
`between the rate of healing of oesophagitis in patients
`with GERD and the duration for which intragastric pH is
`maintained above pH 4.3 The increased duration with
`intragastric pH > 4 observed during esomeprazole ther-
`apy may therefore lead to increased rates of oesophageal
`healing compared with omeprazole. Moreover, predict-
`ability of healing is likely to be increased, relative to
`omeprazole,
`in view of
`the fact
`that
`interpatient
`variability in the pharmacodynamic response is less
`for esomeprazole than for omeprazole. Further compar-
`ative studies are required to determine the clinical
`efficacy,
`in terms of symptom control and rate of
`healing, of esomeprazole in GERD and other acid-related
`diseases.
`tolerated and
`In conclusion, esomeprazole is well
`demonstrates significantly superior acid control com-
`pared to omeprazole, combined with reduced interpa-
`tient variability. Taken together, these findings suggest
`that esomeprazole offers the potential
`for improved
`clinical efficacy in patients with GERD and other acid-
`related diseases.
`
`ACKNOWLEDGEMENTS
`
`This study was sponsored by AstraZeneca R&D, Mo¨ln-
`dal, Sweden.
`
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`
`867
`
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