Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response.

OBJECTIVES: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. METHODS: Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults. RESULTS: Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching Cmax values with adults. CONCLUSIONS: The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposure-response for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.

Prevention of relapse of healed reflux esophagitis is related to the duration of intragastric pH > 4.

Proton pump inhibitors (PPIs) are the preferred treatment for maintenance of healed reflux esophagitis (RE). However, little is known regarding the relationship between prevention of RE relapse and degree of gastric acid suppression. The aim of this review was to examine this relationship in further detail. Data from four comparative studies on maintenance PPI therapy for prevention of relapse of RE were combined with data from two pharmacodynamic studies of duration of intragastric pH >4 during the 24-hour period on day 5 of PPI dosing in healthy subjects. A log-linear model was fitted to the data using the method of maximum likelihood. Variability in relapse rates and pH data was taken into account using a binomial and normal likelihood function, respectively. Pharmacodynamic studies resulted in a wide range of acid-suppressive effect, and based on corresponding maintenance of RE healing rates with different PPIs and doses, an inverse (non-linear) statistically significant relationship between percentage of time with pH >4 and maintenance of RE healing was identified (P<0.001). These findings indicate that long-term maintenance of healed RE is related to the extent of acid suppression in a 24-hour period.

Acid control cannot be improved with a modified-release formulation of a proton pump inhibitor compared with twice-daily dosing of the conventional formulation.

AIM: The aim of this study was to compare acid control with a once-daily (od) modified-release (MR) formulation of esomeprazole vs. the conventional formulation (CF) dosed twice-daily (bid). METHODS: In a randomized, five-way crossover study, 55 healthy volunteers underwent 24-h intragastric pH monitoring after 5-day treatment with MR esomeprazole (40, 60 or 80 mg od) and CF esomeprazole (20 or 40 mg bid). RESULTS: Modified-release 60 and 80 mg od resulted in a significantly longer time with intragastric pH > 4 than MR 40 mg od (77.1 and 79.0% vs. 66.4%, respectively; both p < 0.05). At equivalent total daily doses, CF 20 mg bid led to a significantly longer time with intragastric pH > 4 than MR 40 mg od (72.3 vs. 66.4%; p < 0.05), and CF 40 mg bid led to a significantly longer time with pH > 4 than MR 80 mg od (85.5 vs. 79.0%; p < 0.05). CONCLUSIONS: At equivalent total daily doses, the MR formulation of esomeprazole provides less 24-h acid control than the conventional formulation dosed twice-daily.

Effect of increasing esomeprazole and pantoprazole doses on acid control in patients with symptoms of gastro-oesophageal reflux disease: a randomized, dose-response study.

BACKGROUND AND OBJECTIVE: In patients with gastro-oesophageal reflux disease (GORD), dose escalation or drug switching may be considered in those with symptoms that persist despite standard-dose proton pump inhibitor (PPI) therapy. This study set out to assess whether increasing the dosage of oral esomeprazole and pantoprazole improves acid control in GORD patients, and to compare the pharmacodynamic efficacy of esomeprazole and pantoprazole administered at different dosages. METHODS: This was an open-label, randomized, six-way crossover study that included Helicobacter pylori-negative GORD patients (aged 20-60 years) with <30% of time with intragastric pH>4. Patients were treated with oral once-daily esomeprazole 20 mg, 40 mg and 80 mg, and pantoprazole 20 mg, 40 mg and 80 mg, for 5 days. The main outcome measures were time with intragastric pH>4 over 24 hours, median pH over 24 hours and area under the hydrogen ion versus time curve on day 5 for each treatment period. RESULTS: Dose escalation with both PPIs improved acid control. The proportion of time with intragastric pH>4 (day 5) was 46.7% with esomeprazole 20 mg/day, 58.6% with esomeprazole 40 mg/day, and 65.8% with esomeprazole 80 mg/day; the corresponding percentages with pantoprazole were 28.6%, 36.9% and 44.9%, respectively. On a milligram-per-milligram basis, esomeprazole provided greater acid control than pantoprazole (p<0.001). CONCLUSION: Dose escalation with oral esomeprazole and pantoprazole improves acid control in patients with GORD, although esomeprazole provides significantly greater acid control on a milligram-per-milligram basis.

Intravenous esomeprazole (40 mg and 20 mg) inhibits gastric acid secretion as effectively as oral esomeprazole: results of two randomized clinical studies.

OBJECTIVES: Two studies compared the effects of intravenous (i.v.) and oral esomeprazole (40 mg and 20 mg) on gastric acid suppression and pharmacokinetics after both single (day 1) and repeated (day 5) dosing. METHODS: Two randomized, two-way, cross-over, comparative studies of similar design were performed in healthy male and female volunteers. In both studies, subjects received esomeprazole as a 30-min i.v. infusion or orally once-daily for 5 days, separated by a wash-out period of at least 13 days. In one study, which was double-blind (double dummy), subjects received 40 mg esomeprazole. In the other open study, subjects were given 20 mg esomeprazole. RESULTS: In total, 40 and 24 subjects were randomized for treatment with 40 mg and 20 mg esomeprazole, respectively. No significant differences were found between i.v or oral administration of esomeprazole with respect to the amount of time with mean intragastric pH>4 throughout day 1 or day 5 of treatment in the 40 mg study (day 1, 10.1 h and 8.8 h versus day 5, 15.9 h and 15.3 h, respectively) and the 20 mg study (day 1, 7.3 h and 6.6 h versus day 5, 11.9 h and 12.3 h, respectively). The area under the plasma concentration-time curve values were higher following i.v. relative to oral administration on day 1 of dosing, with less pronounced differences after repeated (day 5) dosing. Both administration routes were similarly well tolerated. CONCLUSIONS: Esomeprazole, 40 mg and 20 mg i.v., provides similar levels of intragastric acid control on both day 1 and day 5 of treatment compared with oral administration.

Pharmacokinetics of esomeprazole following varying intravenous administration rates.

There are situations where the use of an oral proton pump inhibitors is not possible. In such situations an intravenous route is the preferred alternative. An intravenous formulation of esomeprazole has recently been developed. This study was designed to evaluate the pharmacokinetics and tolerability of single-dose intravenous esomeprazole using different rates of administration. The study was an open randomised, cross-over design in healthy male and female (n = 24). Esomeprazole 40 mg intravenously was administrated as an infusion over 10, 15, 20 or 30 min., or esomeprazole 20 mg intravenously as an injection over 3 min. There was a wash-out period of at least 6 days between dose regimens. It was demonstrated that increasing the rate of intravenous infusion of esomeprazole 40 mg resulted in higher Cmax values (geometric means; 5.2-7.6 micromol/l), but the AUC values remained relatively constant (7.1-7.2 micromor/l). As expected esomeprazole 20 mg administered as a 3 min. intravenous injection had lower Cmax (3.6 micromol/l) and AUC (2.9 micromol.r/l) values than any of the infusions of esomeprazole 40 mg. Intravenous esomeprazole was well tolerated in this study. In conclusion, any variation in the infusion rate of esomeprazole 40 mg intravenously has little effect on the pharmacokinetics of esomeprazole in healthy volunteers, which provides flexibility in the choice of dosing regimens.

Intravenous Esomeprazole 40mg is Effective for the Control of Intragastric Acid Levels Whether Given as a 3-Minute Injection or a 30-Minute Infusion.

BACKGROUND: An intravenous (IV) formulation of esomeprazole has been developed as an alternative to oral administration. To meet the needs of different clinical situations it would be preferable if an IV dose could be administered as either an injection or an infusion, while producing similar effects. AIM: To compare the effects of IV esomeprazole 40mg given as a 3-minute injection or a 30-minute infusion on intragastric pH during single and repeated once-daily dosing in healthy subjects. METHODS: In this single-centre, double-blind, double-dummy, randomised, two- way crossover study, subjects were randomised to receive either a 3-minute IV injection or a 30-minute IV infusion of esomeprazole 40mg. Both regimens were given once daily for 10 days. After a washout period of at least 13 days, subjects were crossed over to the other treatment. Intragastric pH monitoring was performed on days 1 and 10. Blood samples were also taken throughout days 1 and 10. RESULTS: Data were available from 41 subjects. Time with intragastric pH >4 was 3.1h/24h at baseline, increasing to almost 8h in association with IV esomeprazole injection or infusion on day 1, and to >13h on day 10. Geometric mean time with pH >4/24h ratios (injection/infusion) were 0.99 on day 1 and 1.03 on day 10. Mean esomeprazole AUC values were approximately 15% higher with the injection than the infusion, but 90% CI limits for geometric mean AUC ratios ranged from 1.07 to 1.23, indicating bioequivalence. CONCLUSIONS: IV esomeprazole 40mg provides similarly potent acid control whether administered by injection or infusion.

Daytime intragastric acid control: post hoc analyses of esomeprazole 20 mg and over-the-counter proton-pump inhibitors.

OBJECTIVES: In mild gastroesophageal reflux disease, which accounts for the great majority of cases, the major burden of reflux occurs during daytime hours, after food intake. The aim of these analyses was to evaluate intragastric pH control during the typical 14-hour daytime awake period by proton-pump inhibitors (PPIs) given at over-the-counter (OTC) dosages. METHODS: In one double-blind and three open-label, randomized, crossover studies, intragastric pH was monitored for 24 hours on day 5 of treatment. The 24-hour data have been reported previously. Post hoc analyses reassessed these studies for the 14-hour daytime period, comparing esomeprazole 20 mg with currently available OTC PPIs omeprazole, pantoprazole (not available in the US) and lansoprazole. RESULTS: Subjects maintained intragastric pH >4 for a significantly greater mean percentage of the 14-hour daytime period with esomeprazole 20 mg compared with any of the PPI comparators at OTC dosages. Geometric mean ratios (95% confidence intervals) for esomeprazole 20 mg versus the comparators were: 1.45 (1.14-1.85; p = 0.003) versus omeprazole 20 mg; 2.50 (2.01-3.11; p < 0.0001) versus pantoprazole 20 mg; and 1.69 (1.46-1.97; p < 0.0001) and 1.89 (1.05-3.37; p = 0.03) versus lansoprazole 15 mg. A greater proportion of subjects had better pH control with esomeprazole than with the other PPIs (range: 69-97%). CONCLUSIONS: Across the 14-hour daytime period, esomeprazole 20 mg once daily given 30 minutes before breakfast for 5 days provided acid control for a significantly greater average proportion of time versus the PPI comparators omeprazole, pantoprazole and lansoprazole at currently available OTC dosages.

Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction.

OBJECTIVE: To examine the pharmacokinetics of omeprazole during intravenous infusion in patients with varying degrees of liver dysfunction (Child-Pugh categories A to C). DESIGN: Nonblinded single-period study. PATIENTS: Thirteen patients, five males and eight females with a mean age of 59 years and proven hepatic cirrhosis, classified according to Child-Pugh criteria as A (n = 5), B (n = 4) or C (n = 4). METHODS: Each patient received an 80mg bolus of omeprazole over 30 minutes followed by a continuous infusion of 8 mg/h for 47.5 hours. Blood samples were taken frequently throughout the infusion and during the subsequent 24-hour washout period for determination of omeprazole and its metabolites. Laboratory screening was also performed at the start of the study, after 72 hours and at the 14 day follow-up visit. RESULTS: Data were evaluable for 12 patients. For omeprazole, the mean total area under the plasma concentration-time curve (AUC) was 286.5 micromol x h/L, peak plasma concentration was 14.9 micromol/L and terminal elimination half-life was 4.1 hours; these values were higher than those observed historically in control patient populations. Concentrations of the metabolite omeprazole sulphone were also increased, but there was a decrease in concentrations of hydroxy-omeprazole. Deviations from normal values increased with increasing disease severity for all parameters. For example, in patients with liver dysfunction of Child-Pugh categories A, B and C, AUC(48 )was 240.8, 280.4 and 323.3 micromol x h/L compared with 151.3 micromol x h/L in the historical control population. Despite its altered pharmacokinetics, omeprazole was not associated with any serious or untoward effects. CONCLUSION: Exposure to omeprazole following intravenous administration was higher in patients with liver dysfunction than in the normal population. However, even in patients with severely impaired liver function, the omeprazole plasma concentration did not change by more than 100% and the drug was well tolerated.

Pharmacokinetic study of esomeprazole in patients with hepatic impairment.

OBJECTIVE: To evaluate the pharmacokinetics and safety of esomeprazole (Nexium), the S-isomer of omeprazole, after repeated oral dosing in patients with hepatic impairment. DESIGN: Single-centre, open-label one-way study. METHODS: Twelve patients (aged 40-60 years) with mild to severe hepatic impairment received once-daily oral esomeprazole 40 mg for 5 days. Serial blood samples were drawn up to 24 h post-dose on day 5 to determine plasma levels of esomeprazole and its metabolites. Pharmacokinetic parameters were compared with an historical control group of 36 gastro-oesophageal reflux disease (GORD) patients (aged 29-58 years) with normal hepatic function. RESULTS: Esomeprazole was absorbed rapidly (mean maximum plasma concentration (Cmax) 6.1 micromol/l, mean time to Cmax (tmax) 1.9 h) and eliminated rapidly (mean plasma elimination half-life (t1/2) 2.1 h). Elimination of its pharmacologically inactive sulphone and hydroxy metabolites was more gradual. Patients with mild hepatic impairment had area under the plasma concentration-time curve during the dosage interval (AUCtau) and t1/2 values largely within the range of the control group. In patients with moderate hepatic impairment, t1/2 values were similar and AUCtau was slightly higher than in controls, whereas both parameters were increased in patients with severe hepatic impairment. The mean ratios of esomeprazole AUCtau, Cmax and t1/2 values in patients with and without hepatic impairment were 1.8, 1.3 and 1.3, respectively. CONCLUSIONS: The steady-state pharmacokinetics of esomeprazole were not altered substantially by mild or moderate hepatic impairment; however, plasma levels of esomeprazole were elevated in severe cases. Thus, dose adjustment appears unwarranted in mild or moderate hepatic impairment, but may be required in some severely impaired patients. Esomeprazole was tolerated well across the spectrum of hepatic impairment.

Esomeprazole 20mg provides more effective intragastric Acid control than maintenance-dose rabeprazole, lansoprazole or pantoprazole in healthy volunteers.

OBJECTIVE: A high proportion of patients with gastro-oesophageal reflux disease experience recurrence of symptoms within a year of initial treatment. The key to preventing relapse is an effective maintenance therapy that maintains intragastric pH >4. This study was conducted to compare the effects on intragastric pH of maintenance doses of four proton pump inhibitors: esomeprazole 20mg, lanso-prazole 15mg, rabeprazole 10mg and pantoprazole 20mg. STUDY PARTICIPANTS AND METHODS: Three standardised, randomised, two-way crossover studies were performed in a total of 108 Helicobacter pylori-negative healthy subjects. Intragastric pH was monitored on day 5 of once-daily oral dosing. The percentage of time of a 24-hour period with intragastric pH >4 and 24-hour median pH were measured on day 5. RESULTS: The mean percentage of time with intragastric pH >4 on day 5 was significantly longer following esomeprazole 20mg compared with either lansoprazole 15mg (esomeprazole 50.4% vs lansoprazole 43.0%, p = 0.026), rabeprazole 10mg (esomeprazole 59.8% vs rabeprazole 51.7%, p = 0.011) or pantoprazole 20mg (esomeprazole 59.6% vs pantoprazole 39.5%, p < 0.0001). CONCLUSIONS: Maintenance dose esomeprazole 20mg provided greater acid control and maintained intragastric pH >4 for a longer period of time than maintenance dose lansoprazole 15mg, rabeprazole 10mg and pantoprazole 20mg in healthy subjects.

Acid control with esomeprazole and lansoprazole: a comparative dose-response study.

OBJECTIVE: To determine the level of acid control and the dose-response relationships achieved with esomeprazole and lansoprazole. These data are relevant in helping clinicians to decide on whether to increase a proton-pump inhibitor dose, or whether to switch to an alterative drug for increased acid control. MATERIAL AND METHODS: In an open-label, single-centre, randomized, six-way crossover study, 40 healthy subjects received esomeprazole 20, 40 and 80 mg, and lansoprazole 15, 30 and 60 mg once daily for 5 days. The mean time with intragastric pH >4 and mean 24-h median intragastric pH on day 5 were analyzed using a mixed-model ANOVA. Post-hoc analyses were completed for 0-12-h (daytime) and 12-24-h (night-time) post-dose intervals. RESULTS: Increasing the dose of esomeprazole from 20 mg to 40 mg resulted in significantly improved acid control over 0-12, 12-24 and 0-24 h post-dose (p<0.001), but no significant improvement in acid control for either period was seen when further increasing the dose to 80 mg. Increasing the dose of lansoprazole from 15 mg to 30 mg or from 30 mg to 60 mg significantly improved acid control over 0-12 and 0-24 h (p<0.01) but not over 12-24 h. With the exception of the esomeprazole 20 mg versus lansoprazole 30 mg comparisons, and the esomeprazole 20 mg versus lansoprazole 15 mg during 12-24 h post-dose comparison, esomeprazole provided significantly greater acid control than lansoprazole at each dose level over 0-12, 12-24 and 0-24 h (p<0.05). Mean 24-h median intragastric pH was higher following esomeprazole dosing compared with lansoprazole at each dose level. CONCLUSIONS: For low-, standard- and double-dose comparisons, esomeprazole achieved greater elevation of gastric pH and better acid control in more subjects than lansoprazole. Use of esomeprazole may therefore reduce the need for dose adaptations or drug switching.

Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reflux disease.

Maintenance of intragastric pH > 4 is vital for effective management of gastroesophageal reflux disease (GERD). Esomeprazole 40 mg, the first proton pump inhibitor developed as an optical isomer, demonstrates improved acid inhibition over omeprazole 20 mg. Our aim was to compare esomeprazole 40 mg with omeprazole 40 mg, once-daily, on intragastric acidity in patients with symptoms of GERD. In this open-label, crossover study, 130 patients with symptoms of GERD received esomeprazole 40 mg or omeprazole 40 mg once-daily for five days. The 24-hr intragastric pH was monitored on days 1 and 5 of each treatment period. The mean percentage of the 24-hr period with intragastric pH > 4 was significantly greater (P < 0.001) with esomeprazole 40 mg than with omeprazole 40 mg on days 1 (48.6% vs 40.6%) and 5 (68.4% vs 62.0%). Interpatient variability was significantly less with esomeprazole than omeprazole. Esomeprazole was well tolerated. In conclusion, esomeprazole 40 mg provides more effective acid control than twice the standard dose of omeprazole.

Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms.

OBJECTIVE: To compare the effect of esomeprazole 40 mg with lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg on intragastric pH during single and repeated dosing in four separate studies in patients with symptoms of gastro-oesophageal reflux disorder (GERD). METHODS: In four randomised crossover studies, patients with symptoms of GERD received once-daily treatment with esomeprazole 40 mg or lansoprazole 30 mg (study A), omeprazole 20 mg (study B), pantoprazole 40 mg (study C) and rabeprazole 20 mg (study D) for 5 days. Continuous 24-h intragastric pH recording was performed on days 1 (except study B) and 5. Percentage of time over 24 h with intragastric pH greater than 4, 24-h median pH and the proportion of patients with pH greater than 4 for greater than or equal to 12 h and 16 h during the 24-h recording periods were investigated. RESULTS: In all four studies, esomeprazole 40 mg OD maintained intragastric pH greater than 4 for a significantly higher mean percentage of the 24-h period compared with all other proton pump inhibitors (PPIs) on days 1 (esomeprazole 40.6% versus lansoprazole 33.4%, P=0.0182; esomeprazole 50.3% versus pantoprazole 29.1%, P<0.001; esomeprazole 41.0% versus rabeprazole 29.4%, P=0.002) and 5 (esomeprazole 57.7% versus lansoprazole 44.5%, P<0.0001; esomeprazole 69.8% versus omeprazole 43.7%, P<0.0001; esomeprazole 67.0% versus pantoprazole 44.8%, P<0.001; esomeprazole 59.4% versus rabeprazole 44.5%, P<0.0001). Higher 24-h median pH and a higher proportion of patients with intragastric pH greater than 4 for greater than or equal to 12 h and 16 h were reported with esomeprazole 40 mg OD than with all the other PPIs in each study. CONCLUSION: Esomeprazole 40 mg provides greater acid control in more patients and maintains intragastric pH greater than 4 for a longer period than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with symptoms of GERD.

Esomeprazole 40 mg provides improved intragastric acid control as compared with lansoprazole 30 mg and rabeprazole 20 mg in healthy volunteers.

AIM: To compare the effects of standard-dose esomeprazole with those of standard doses of lansoprazole and rabeprazole on intragastric pH during repeated daily oral dosing in healthy volunteers. METHODS: In two standardized, randomized crossover studies, Helicobacter pylori negative healthy volunteers (study A: 19 males, 5 females; study B: 13 males, 10 females) received esomeprazole 40 mg and either lansoprazole 30 mg (study A) or rabeprazole 20 mg (study B) orally once daily in the morning for 5 days. Continuous 24-hour intragastric pH recording was performed on day 5. RESULTS: The intragastric pH was maintained >4 for 65% (95% CI 59.5-71.3) of the 24-hour period with esomeprazole and for 53% of the time (95% CI 47.0-58.9) with lansoprazole in study A (p < 0.001). In study B, the proportion of time with pH >4 was 61% (95% CI 53.6-68.3) with esomeprazole versus 45% (95% CI 37.7-52.5) with rabeprazole (p = 0.005). The 24-hour median pH and the proportion of volunteers with intragastric pH >4 for > or =12 h and > or =16 h were significantly higher with esomeprazole than with either lansoprazole or rabeprazole. CONCLUSION: Esomeprazole 40 mg provides significantly more effective and more sustained gastric acid control than lansoprazole 30 mg or rabeprazole 20 mg in healthy volunteers.