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.

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.

A new esomeprazole packet (sachet) formulation for suspension: in vitro characteristics and comparative pharmacokinetics versus intact capsules/tablets in healthy volunteers.

BACKGROUND: A packet (sachet) formulation of esomeprazole for suspension has been developed for use in patients who have difficulty swallowing. OBJECTIVES: This article reports the in vitro characteristics of the new esomeprazole formulation, including stability in suspension and suitability for administration orally or via enteral tubes. It also describes the pharmacokinetic profile of the esomeprazole 40-mg packet compared with that of existing solid dosage forms (capsules and tablets) in a clinical bioequivalence study. METHODS: The stability in suspension of the packet formulation was assessed after reconstitution at various strengths (2.5, 10, and 40 mg) and a different pH (3.4-5.0) in strength-appropriate volumes of water held at temperatures ranging from 5 degrees C to 37 degrees C for up to 60 minutes. Suitability for oral administration was examined in terms of reconstitution time and the actual dose delivered after simulated oral administration, as well as in terms of the actual dose delivered by enteral tubes ranging in diameter from 6 to 20 Fr. Chemical stability and suspension characteristics were also analyzed using alternative reconstitution vehicles (applesauce, apple juice, and orange juice). The comparative pharmacokinetics of the packet, capsule, and tablet formulations of esomeprazole were evaluated in a randomized, open-label, 3-way crossover study in healthy volunteers, who received single 40-mg doses of each formulation. Bioequivalence was assumed if the 90% CIs for the ratios of the geometric mean AUC and CmaX were between 0.80 and 1.25. Reversephase liquid chromatography with ultraviolet detection was used to assess the esomeprazole content and/or degradation products of esomeprazole in the tests for in-suspension stability, dose delivery, and acid resistance. Normal-phase liquid chromatography was used to assess the esomeprazole content of the plasma samples in the bioequivalence study. RESULTS: At the pH and temperature ranges investigated, the packet formulation was stable for up to 60 minutes after reconstitution. Chemical degradation was low (<0.1%) for all reconstitution vehicles investigated. Reconstitution time was 2 minutes with water and 9 to 10 minutes with apple or orange juice. Dose delivery was >/=98% after simulated oral administration and was generally >/=96% after administration via enteral tubes. Ninety-six healthy volunteers (56 women, 40 men; mean age, 24.9 years; mean weight, 68.9 kg) participated in the randomized, crossover, comparative pharmacokinetic study of the packet and capsule/tablet formulations. The estimated ratios of the geometric mean AUC and C(max) for the packet:capsule and packet: tablet formulations were 0.98 (90% CI, 0.93-1.03) and 0.99 (90% CI, 0.94-1.04), respectively. CONCLUSIONS: In these analyses, the packet (sachet) formulation of esomeprazole was chemically stable in suspension and when administered orally and via enteral tubes. The formulation had a short reconstitution time, remaining fully dispersed in water for at least 30 minutes, and was dispersed in applesauce, apple juice, or orange juice without compromising its stability or dispersion characteristics. The packet formulation met the regulatory definition for bioequivalence to the tablet and capsule formulations.