Pharmacokinetics and Acid-suppressive Effects of Esomeprazole in Infants 1-24 Months Old With Symptoms of Gastroesophageal Reflux Disease.

OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and ≥ 5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH >4 and intraesophageal pH <4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH <4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of >5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 µmol · h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD.

Pharmacokinetics and Acid-suppressive Effects of Esomeprazole in Infants 1-24 Months Old With Symptoms of Gastroesophageal Reflux Disease.

OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and ≥ 5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH > 4 and intraesophageal pH < 4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH < 4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of > 5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 µmol · h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD.

Sensitization to omeprazole in the occupational setting.

BACKGROUND: Omeprazole is a proton pump inhibitor for the treatment of gastric acid-related disorders. In recent years, reports of dermatitis upon exposure to omeprazole during manufacture have been noted. OBJECTIVE: To present diagnostic findings in workers who reported suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. METHODS: Ninety-six workers exposed to omeprazole during the manufacturing process underwent investigation by the AstraZeneca Occupational Health Centre (Södertälje, Sweden) for suspected allergy. All subjects underwent a lymphocyte transformation test (LTT) and a skin test within 6 months of the clinical reaction. Predictive tests on guinea-pigs were conducted to establish omeprazole's sensitizing potential. RESULTS: Thirty-one subjects with clinical symptoms had a positive LTT result. Twenty-eight subjects had positive patch test results; of these, 23 also had a positive LTT result (sensitivity of the LTT: 82%). Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result (specificity: 82%). All subjects who underwent prick testing (n = 18) had negative results. Delayed contact hypersensitivity was observed in 18 of 20 test animals. CONCLUSIONS: These findings confirm the risk of sensitization to omeprazole from occupational exposure. They are of importance for the development of new formulations of omeprazole, or its enantiomers, in light of the potential for inducing skin allergy.

Single-dose pharmacokinetic properties of esomeprazole in children aged 1 - 11 years with endoscopically proven GERD: a randomized, open-label study.

OBJECTIVE: To assess the overall exposure after a single dose of esomeprazole in children with gastroesophageal reflux disease (GERD). MATERIALS: Oral esomeprazole administered as an intact capsule with 30 - 180 mL of water, or as an opened capsule mixed with as much as 1 tablespoon of applesauce followed by 30 - 180 mL of water. METHODS: In this randomized, open-label study of children aged 1 - 11 years with endoscopically proven GERD, patients weighing 8 - < 20 kg were randomized to a single 5- or 10-mg oral dose of esomeprazole, and patients weighing >= 20 kg were randomized to a single 10- or 20-mg oral dose of esomeprazole. Esomeprazole exposure (AUC(0-∞)), AUC from zero to last measurable concentration (AUC(0-t)), maximum plasma concentration (C(max)), time to C(max) (t(max)), terminal-phase half-life, apparent oral clearance, and apparent volume of distribution were determined. RESULTS: 28 patients were randomized to receive esomeprazole: 14 patients weighing 8 to < 20 kg received esomeprazole 5 mg (n = 7) or 10 mg (n = 7), and 14 patients weighing ≥20 kg received esomeprazole 10 mg (n = 6) or 20 mg (n = 8). Children weighing 8 - < 20 kg had a 1.8-fold higher exposure with the 10-mg vs. 5-mg dose (AUC(0-∞), 1.32 vs. 0.73 µmol·h/L, respectively); children weighing ≥ 20 kg had a 4.4-fold higher exposure with the 20-mg vs. 10-mg dose (AUC(0-∞), 3.06 vs. 0.69 µmol·h/L). C(max) was 2.2-fold higher for the 10-mg vs. 5-mg dose (8 to < 20 kg) and 2.4-fold higher for the 20-mg vs.10-mg dose (>= 20 kg). CONCLUSIONS: The pharmacokinetics of single-dose esomeprazole were dose-dependent in children weighing >= 20 kg but not in children weighing 8 to < 20 kg.

Efficacy and safety of once-daily esomeprazole for the treatment of gastroesophageal reflux disease in neonatal patients.

OBJECTIVE: To evaluate the efficacy and safety of proton pump inhibitors in infants aged <1 year with gastroesophageal reflux disease (GERD). STUDY DESIGN: In this randomized, double-blind, placebo-controlled multicenter study, neonates (premature to 1 month corrected age; n = 52) with signs and symptoms of GERD received esomeprazole 0.5 mg/kg or placebo once daily for up to 14 days. Change from baseline in the total number of GERD symptoms (from video monitoring) and GERD-related signs (from cardiorespiratory monitoring) was assessed with simultaneous esophageal pH, impedance, cardiorespiratory, and 8-hour video monitoring. RESULTS: There were no significant differences between the esomeprazole and placebo groups in the percentage change from baseline in the total number of GERD-related signs and symptoms (-14.7% vs -14.1%, respectively). Mean change from baseline in total number of reflux episodes was not significantly different between esomeprazole and placebo (-7.43 vs -0.2, respectively); however, the percentage of time pH was <4.0 and the number of acidic reflux episodes >5 minutes in duration was significantly decreased with esomeprazole vs placebo (-10.7 vs 2.2 and -5.5 vs 1.0, respectively; P ≤ .0017). The number of patients with adverse events was similar between treatment groups. CONCLUSIONS: Signs and symptoms of GERD traditionally attributed to acidic reflux in neonates were not significantly altered by esomeprazole treatment. Esomeprazole was well tolerated and reduced esophageal acid exposure and the number of acidic reflux events in neonates.

Phase I, multicenter, randomized, open-label study evaluating the pharmacokinetics and safety profile of repeated once-daily doses of intravenous esomeprazole in children 0 to 17 years of age.

BACKGROUND: Several oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children. OBJECTIVE: The aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children. METHODS: In this multicenter, open-label study, hospitalized patients (0-17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0-1 month of age), 1.0 mg/kg (1-11 months of age), 10 mg (1-5 years of age), 10 or 20 mg (6-11 years of age), or 20 or 40 mg (12-17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed. RESULTS: Fifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC(τ) ranged from 6.9 µmol · h/L (10 mg, 6-11 years) to 17.6 µmol · h/L (40 mg, 12-17 years). The mean C(ss,max) ranged from 3.7 µmol/L (0.5 mg/kg, 0-1 month) to 10.5 µmol/L (40 mg, 12-17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs. CONCLUSIONS: Intravenous esomeprazole at doses resulting in targeted AUC(τ) and C(ss,max) similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019.

Incidence of peptic ulcer bleeding in the US pediatric population.

OBJECTIVES: The aim of the present study was to determine the incidence of peptic ulcer bleeding (PUB) in pediatric patients. METHODS: A hospital inpatient database, Premier Perspective, and an insurance claims database, MarketScan, were analyzed to estimate upper and lower limits for the annual incidence of PUB in the US pediatric population. RESULTS: Using data from the Premier Perspective database and database-specific projection methodology, the total number of cases of hospitalization of pediatric patients for PUB in the United States in 2008 was estimated to be between 378 and 652. This translated to an incidence of 0.5 to 0.9/100,000 individuals in the pediatric population. Using data from the MarketScan database, the incidence of PUB in the insured pediatric population was estimated to be 4.4/100,000 individuals. Overall, 17.4% of insured pediatric patients diagnosed as having any upper gastrointestinal ulcer in 2008 were reported to have developed PUB. CONCLUSIONS: The estimated incidence of PUB in the US pediatric population in 2008 ranged from 0.5 to 4.4/100,000 individuals. The total number of cases of PUB in pediatric patients in the United States each year was thus estimated to be between 378 and 3250. Such estimates provide a likely lower and upper limit for the total number of cases of the condition annually.

Treatment patterns in paediatric patients with a new diagnosis of gastroesophageal reflux disease.

OBJECTIVE: Few data exist on the treatment of gastroesophageal reflux disease (GERD) in paediatrics. The objective of this study was to examine treatment patterns of GERD in paediatrics in the primary care. METHODS: Incident GERD cases among paediatric patients were identified using The Health Improvement Network UK primary care database. We assessed prescription treatments in 30 days before and any time after the date of diagnosis. Initial treatment was defined as that received in 30 days either side of diagnosis. Odds ratios and 95% confidence intervals of receiving the treatment were calculated by multiple logistic regressions. RESULTS: The incident GERD cohort comprised 1700 paediatric patients aged 1-17 years. Antacids were initially prescribed in 49.2% of patients. Similar proportions of patients (23.3 and 22.9%) received histamine-2 receptor antagonists (H(2)RAs) and proton pump inhibitors (PPIs); 7.5% were prescribed prokinetics and 19.3% received no prescribed treatment. Overall, 24.7% of initial H(2)RA users switched to PPIs, and 9.8% of those using PPIs switched to H(2)RAs. The likelihood of the use of PPI increased with age and was lower in girls than in boys (odds ratio: 0.7; 95% confidence interval: 0.5-0.9). CONCLUSIONS: Antacids are the drugs most frequently prescribed by primary care physicians to paediatric patients with GERD, and approximately half receive an initial course of antisecretory treatment with H(2)RAs or PPIs. This study suggests that treatment patterns in paediatrics differ from those in adults.

Maintenance treatment with proton pump inhibitors for reflux esophagitis in pediatric patients: a systematic literature analysis.

OBJECTIVES: Short-term treatment with a proton pump inhibitor (PPI) is effective for healing reflux esophagitis and improving reflux symptoms in pediatric patients. Our aim was to assess the efficacy and tolerability of maintenance PPI treatment after healing of reflux esophagitis in pediatric patients. MATERIALS AND METHODS: Systematic searches of MEDLINE, Excerpta Medica database, and recent conference abstracts. RESULTS: Five studies evaluated the efficacy of PPI maintenance therapy (6- to 90-month follow-up) in pediatric patients after healing of reflux esophagitis. Three found no relapse of reflux esophagitis or reflux symptoms during PPI maintenance therapy; however, a low relapse rate (1/14) was also found in the placebo group of the only prospective controlled study. Two of the 5 studies (both prospective) reported relapse of reflux esophagitis at half the original healing dose of omeprazole (7 of 51 patients relapsed after 3 months; 8 of 32 within 21 months), which resolved again in most patients when the healing dose or higher was given. Four studies evaluated relapse of reflux esophagitis and/or reflux symptoms after stopping PPI therapy. Reflux symptoms recurred in 18% to 76% of patients across all 4 studies. In the 4 studies that assessed the safety of PPI maintenance therapy, adverse events were infrequent and of low severity. CONCLUSIONS: Pediatric patients with gastroesophageal reflux disease and certain chronic comorbidities appear to have the greatest need of maintenance PPI treatment after healing of reflux esophagitis. In patients requiring maintenance therapy, PPIs appear to be well tolerated and effective in maintaining remission of reflux esophagitis and reflux symptoms.

Follow-up of a cohort of children and adolescents with gastro-esophageal reflux disease who were free of reflux esophagitis at initial diagnosis.

OBJECTIVE: Few studies have examined the incidence of complications from gastro-esophageal reflux disease (GERD) in children and adolescents in primary care. Here we aimed to describe the natural history of GERD in a pediatric population with no reflux esophagitis at initial diagnosis, assessing diagnoses of new esophageal complications and extra-esophageal conditions. MATERIAL AND METHODS: We used The Health Improvement Network UK primary care database (which includes data on more than 2 million patients) to identify individuals aged 1-17 years with a first diagnosis of gastro-esophageal reflux or heartburn in the period 2000-2005, via a computerized search followed by a manual review of the patient records. This search identified 1242 individuals with an incident diagnosis of GERD but no record of esophagitis. This cohort was followed-up to detect new diagnoses of esophageal complications and extra-esophageal conditions. RESULTS: During a mean follow-up period of almost 4 years, 40 children and adolescents had a confirmed new diagnosis of reflux esophagitis (incidence: 10.9 per 1000 person-years). No cases of Barrett's esophagus, esophageal stricture or esophageal ulcer were reported. Individuals with GERD had double the risk of an extra-esophageal condition such as asthma, pneumonia, cough or chest pain compared with children and adolescents with no diagnosis of GERD. CONCLUSIONS: Children and adolescents with GERD may be at risk of developing reflux esophagitis and a range of other extra-esophageal conditions, but more severe esophageal complications are rare.

Gastroesophageal reflux disease in children and adolescents in primary care.

OBJECTIVES: To determine the prevalence and incidence of a diagnosis of gastroesophageal reflux disease (GERD) in children and adolescents in UK primary care, and to assess comorbidities that are associated with a diagnosis of GERD. MATERIAL AND METHODS: Incident GERD cases during 2000-05 were identified from The Health Improvement Network (THIN) UK primary care database via a computer search for diagnostic codes for GERD, followed by manual review of the patient records. RESULTS: We identified 1700 children with a first diagnosis of GERD during 2000-05. The incidence of GERD was 0.84 per 1000 person-years. The incidence decreased with age from 1.48 per 1000 person-years among 1-year-old children until the age of 12 years, whereupon it increased to a maximum at 16-17 years of 2.26 per 1000 person-years for girls and 1.75 per 1000 person-years for boys. Pregnant adolescents were not included in the study. In addition to typical GERD symptoms (epigastric pain, heartburn, reflux, regurgitation), 21.2% of children reported nausea or vomiting. Children with neurological disorders were at increased risk of a GERD diagnosis. Hiatus hernia and congenital esophageal disorders were also associated with a diagnosis of GERD. Children and adolescents using antiepileptics, oral/inhaled steroids, beta-agonists and paracetamol had an increased risk of a GERD diagnosis. CONCLUSIONS: The incidence of a GERD diagnosis was age-dependent and was highest among very young children and older female adolescents. Children with neurological impairments and other comorbidities were at increased risk of a GERD diagnosis.

Pharmacodynamics and systemic exposure of esomeprazole in preterm infants and term neonates with gastroesophageal reflux disease.

OBJECTIVE: To characterize the pharmacodynamics and systemic exposure of esomeprazole in 26 preterm infants and term neonates with symptoms of gastroesophageal reflux and pathologic acid exposure. STUDY DESIGN: Enrolled patients received oral esomeprazole 0.5 mg/kg once daily for 7 days. Twenty-four-hour esophagogastric pH-impedance monitoring was performed at baseline and on day 7. Pharmacokinetic analysis was performed on day 7. Symptoms occurring during the baseline and day 7 studies were recorded on a symptom chart. RESULTS: There were no significant differences from baseline to day 7 of therapy in the frequency of bolus reflux, consistency of bolus reflux (liquid, mixed, or gas), extent of bolus reflux, or bolus clearance time. Acid bolus reflux episodes were reduced on therapy (median 30 vs 8, P < .001), as was the reflux index (mean % time esophageal pH < 4, 15.7% vs 7.1%, P < .001). The estimated geometric mean of area under the plasma concentration time curve during the dosing interval and observed maximum plasma concentration was 2.5 micromol x h/L and 0.74 micromol/L, respectively. The number of gastroesophageal reflux symptoms recorded over 24 hours was lower on therapy (median 22 vs 12, P < .05). CONCLUSIONS: In preterm infants and term neonates esomeprazole produces no change in bolus reflux characteristics despite significant acid suppression.

A randomized, comparative trial of a potassium-competitive acid blocker (AZD0865) and esomeprazole for the treatment of patients with nonerosive reflux disease.

OBJECTIVES: AZD0865 is a gastric acid-suppressing agent that has a rapid onset of action and long duration of effect. This double-blind, randomized, multicenter study investigated the efficacy and safety of AZD0865 in the treatment of patients with nonerosive reflux disease (NERD). METHODS: Patients with troublesome heartburn for at least 6 months and no evidence of erosions at endoscopy were randomized to receive AZD0865 (25, 50, or 75 mg/day) or esomeprazole 20 mg/day, for 4 wk. Throughout the treatment period, patients reported the presence and intensity of heartburn and other NERD symptoms twice daily using an electronic diary. Twenty-four-hour ambulatory intraesophageal/intragastric pH monitoring was performed in a subset of patients on day 14. RESULTS: A total of 1,469 patients were randomized. The median time to sustained absence of heartburn (for 7 consecutive days) was approximately 12 days for all treatment groups and did not differ significantly for any of the AZD0865 doses or compared with esomeprazole. There were no significant differences among treatment groups in the cumulative incidence of sustained absence of heartburn during 4 wk treatment (i.e., 65-70%). The percentage of time for which intragastric pH was greater than 4 was significantly greater for AZD0865 75 mg/day compared with esomeprazole 20 mg (75% vs 60%, P < 0.05). AZD0865 was generally well tolerated although reversible elevations of liver transaminases occurred in some patients receiving the agent. CONCLUSIONS: AZD0865 did not provide clinical benefit over esomeprazole 20 mg in the management of patients with NERD.

Pharmacokinetics and acid-suppressive effects of esomeprazole in infants 1-24 months old with symptoms of gastroesophageal reflux disease.

OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and >or=5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH >4 and intraesophageal pH <4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH <4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of >5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 micromol x h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD.

Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux.

INTRODUCTION: Proton pump inhibitor (PPI) therapy is increasingly being used to treat premature infants with gastroesophageal reflux disease (GERD); however, the efficacy of PPI on acid production in this population has yet to be assessed in this patient group. The aim of this study was to determine the effect of 0.7 mg/kg/d omeprazole on gastric acidity and acid gastroesophageal reflux in preterm infants with reflux symptoms and pathological acid reflux on 24-h pH probe. METHODS: A randomized, double blind, placebo-controlled, crossover design trial of omeprazole therapy was performed in 10 preterm infants (34-40 weeks postmenstrual age). Infants were given omeprazole for 7 d and then placebo for 7 d in randomized order. Twenty-four-hour esophageal and gastric pH monitoring was performed on days 7 and 14 of the trial. RESULTS: Compared to placebo, omeprazole therapy significantly reduced gastric acidity (%time pH <4, 54% vs 14%, P < 0.0005), esophageal acid exposure (%time pH <4, 19% vs 5%, P < 0.01) and number of acid GER episodes (119 vs 60 episodes, P < 0.05). CONCLUSIONS: Omeprazole is effective in reducing esophageal acid exposure in premature infants with pathological acid reflux on 24-h pH probe; however, the far more complex issues of safety and efficacy have yet to be addressed.

Pharmacokinetic properties of esomeprazole in adolescent patients aged 12 to 17 years with symptoms of gastroesophageal reflux disease: A randomized, open-label study.

OBJECTIVE: The aim of this study was to assess the pharmacokinetic (PK) properties and tolerability of esomeprazole 20 and 40 mg after single and repeated oral doses in adolescents with symptoms of gastroesophageal reflux disease (GERD). RESULTS: The study included 15 boys and 13 girls (mean age, 14.3 years). Geometric mean AUC(0-infinity) values (overall drug exposure) were 1.58 and 5.57 micromol . h/L (0.027 and 0.083 pmol x h x L(-1)/kg) after single-dose administration of esomeprazole 20 and 40 mg, respectively, on day 1. Corresponding values with repeated doses (day 8) were 3.65 and 13.86 micromol x h/L (0.064 and 0.207 micromol x h x L(-1)/kg). Geometric mean Cmax values were 0.67 and 2.78 micromol/L (0.012 and 0.041 micromol/L x kg(-1)) with single-dose administration of esomeprazole 20 and 40 mg, respectively, and 1.45 and 5.13 micromol/L (0.026 and 0.075 micromol/L x kg(-1)), respectively, with repeated doses (day 8). These mean AUC(0-infinity) and CmaX values were >2-fold with the 40 mg dose compared with the 20-mg dose with single- and repeated-dose administration. The most common adverse event was headache (2 [7.1%] patients). CONCLUSIONS: The results of this study suggest that the PK parameters of esomeprazole were both dose- and time-dependent in these adolescents with GERD. Both doses of esomeprazole were well tolerated in this study population.

Pharmacokinetic properties of esomeprazole in children aged 1 to 11 years with symptoms of gastroesophageal reflux disease: a randomized, open-label study.

OBJECTIVE: The aim of this study was to assess the overall exposure, other pharmacokinetic (PK) properties, and tolerability of esomeprazole magnesium after repeated oral doses of 5, 10, and 20 mg in pediatric patients who had symptoms of gastroesophageal reflux disease (GERD). METHODS: This randomized, open-label study was conducted at West Coast Clinical Trials, Long Beach, California. Boys and girls aged 1 to 11 years who had a clinical diagnosis of GERD were included and stratified by age (1-5 years [younger group] and 6-11 years [older group]). For this 5-day study, children in the younger group were randomly assigned to receive 1 esomeprazole 5- or 10-mg capsule p.o. QD, and those in the older group were randomly assigned to receive 1 esomeprazole 10- or 20-mg capsule p.o. QD. On days 1 to 4, study medications were administered with the supervision of the study personnel 1 hour before breakfast. Blood samples were collected within 0.5 hour before and 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours after study drug administration on day 5. Plasma concentrations of esomeprazole were measured using reverse-phase liquid chromatography and mass-spectrometric detection. Tolerability assessments were performed by reviewing the number and severity of adverse events (collected via spontaneous reporting and direct questioning) and findings from the physical examination, which included vital-sign measurements and laboratory analysis (hematology, biochemistry, and urinalysis). Site personnel supervised the administration of the study drug to ensure compliance with treatment. RESULTS: The study included 31 children (17 boys, 14 girls; mean age, 5 years; 18 children in the younger group, 13 in the older group). A total of 27 children were included in the PK analysis. In the younger group, the geometric mean AUC(0-infinity) and Cmax values in the esomeprazole 10-mg group were >2-fold that in the 5-mg group (AUC(0-infinity), 4.83 and 0.74 pmol x h/L [0.32 and 0.04 micromol x h x L(-1)/kg], respectively; Cmax, 2.98 and 0.62 micromol/L [0.19 and 0.03 micromol/L x kg(-1)], respectively). In the older group, the geometric mean AUC(0-infinity) and Cmax values for the 20-mg dose group were approximately 2-fold those for the 10-mg dose group (AUC(0-infinity), 6.28 and 3.70 micromol x h/L [0.21 and 0.12 pmol x h x L(-1)/kg], respectively; Cmax, 3.73 and 1.77 micromol/L [0.13 and 0.06 micromol/L x kg 1], respectively). For the 10-mg esomeprazole dose, the geometric mean body-weight-normalized apparent oral clearance was approximately 50% higher in the younger group compared with the older group (0.40 and 0.25 L/h x kg(-1), respectively). Thirty patients were included in the tolerability analysis. The adverse events that occurred were skin excoriation, discolored feces, and skin laceration (1 [3.3%] patient each); none were considered related to treatment. CONCLUSIONS: The results of this small study suggest that, in children aged 1 to 11 years who had GERD, the PK properties of esomeprazole may be both dose and age dependent and that younger children might have a more rapid metabolism of esomeprazole per kilogram of body weight compared with older children. Esomeprazole was well tolerated at doses of 5, 10, and 20 mg in the pediatric patients studied.