Stuart Atkinson

Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease.

OBJECTIVE To assess the efficacy and safety of lansoprazole in treating infants with symptoms attributed to gastroesophageal reflux disease (GERD) that have persisted despite a >or= 1-week course of nonpharmacologic management. STUDY DESIGN This multicenter, double-blind, parallel-group study randomized infants with persisting symptoms attributed to GERD to treatment with lansoprazole or placebo for 4 weeks. Symptoms were tracked through daily diaries and weekly visits. Efficacy was defined primarily by a >or= 50% reduction in measures of feeding-related crying and secondarily by changes in other symptoms and global assessments. Safety was assessed based on the occurrence of adverse events (AEs) and clinical/laboratory data. RESULTS Of the 216 infants screened, 162 met the inclusion/exclusion criteria and were randomized. Of those, 44/81 infants (54%) in each group were responders--identical for lansoprazole and placebo. No significant lansoprazole-placebo differences were detected in any secondary measures or analyses of efficacy. During double-blind treatment, 62% of lansoprazole-treated subjects experienced 1 or more treatment-emergent AEs, versus 46% of placebo recipients (P= .058). Serious AEs (SAEs), particularly lower respiratory tract infections, occurred in 12 infants, significantly more frequently in the lansoprazole group compared with the placebo group (10 vs 2; P= .032). CONCLUSIONS This study detected no difference in efficacy between lansoprazole and placebo for symptoms attributed to GERD in infants age 1 to 12 months. SAEs, particularly lower respiratory tract infections, occurred more frequently with lansoprazole than with placebo.

Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation – results from two randomized controlled studies

Background  Dexlansoprazole MR employs a dual delayed‐release delivery system that extends drug exposure and prolongs pH control compared with lansoprazole.

Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials.

ABSTRACT Background: Dexlansoprazole MR is a novel Dual Delayed Release formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing. Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR. Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n = 40), subjects received dexlansoprazole MR 60, 90, and 120 mg and lansoprazole 30 mg QD. In study 2 (n = 45), subjects received dexlansoprazole MR 30 and 60 mg and lansoprazole 15 mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure. Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma concentration–time profile following administration of dexlansoprazole MR was characterized by two distinct peaks and a prolonged drug exposure during the 24-h dosing interval. Approximate dose proportionality was observed for mean peak plasma concentration and area under the plasma–concentration time curve after administration of dexlansoprazole MR. In each study, doses of dexlansoprazole MR generally produced greater gastric acid suppression than lansoprazole. Based on the exposure–response analysis using combined data from these two trials, the predicted mean 24-h intragastric pH values were 4.06 and 4.35 for the dexlansoprazole MR 30- and 90-mg doses, respectively. The percent of time pH > 4 over 24 h values were 59.2% and 66.7% for dexlansoprazole MR 30 and 90 mg, respectively. No appreciable additional gain in the pharmacodynamic response was predicted for dexlansoprazole MR 120 mg. Despite combining data from two studies to evaluate a broader dose range, this analysis provided a reasonable estimate of the pharmacodynamic parameters and a good characterization of the dexlansoprazole MR exposure–response relationship. Conclusions: Dexlansoprazole MR, a proton pump inhibitor that uses Dual Delayed Release technology, produced a pharmacokinetic profile with a plasma concentration–time curve characterized by two distinct peaks and an extended duration of pharmacologically active dexlansoprazole concentration in plasma. Exposure–response analysis indicated a progressive increase in the pharmacodynamic response as dexlansoprazole MR doses increased from 30 to 90 mg.

The effect of time-of-day dosing on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR: evidence for dosing flexibility with a Dual Delayed Release proton pump inhibitor

Aliment Pharmacol Ther 31, 1001–1011

The clinical safety of long‐term lansoprazole for the maintenance of healed erosive oesophagitis

Background  The clinical safety of long‐term lansoprazole therapy for the maintenance of healed erosive oesophagitis has not been extensively studied in clinical trials.

Helicobacter pylori-negative gastritis in erosive esophagitis, nonerosive reflux disease or functional dyspepsia patients.

Background Although Helicobacter pylori infection is believed to be the main cause of chronic gastritis, a US clinical trial investigating the long-term effects of lansoprazole as maintenance therapy for erosive esophagitis revealed a surprisingly high prevalence (over 90%) and severity of chronic gastritis in H. pylori-negative subjects. Goals This study aims to compare prevalence and severity of chronic gastritis of the body and antrum in H. pylori-negative subjects with erosive esophagitis, nonerosive reflux disease, or functional dyspepsia from several trials. Study Pretreatment gastric histology was compared in 1595 H. pylori-negative subjects with erosive esophagitis (≥ grade 2; n=196), nonerosive reflux disease (n=688), or functional dyspepsia (n=711) who participated in US Takeda-sponsored lansoprazole trials. Results Pretreatment histology data from US clinical studies showed that 67.5% and 75.0% of H. pylori-negative adult subjects with erosive esophagitis had moderate or severe body and antral chronic gastritis, respectively. Chronic gastritis was also observed in H. pylori-negative subjects with nonerosive reflux disease or functional dyspepsia, although prevalence was significantly less (P<0.001) than in erosive esophagitis. Conclusions Chronic gastritis in H. pylori-negative subjects is more common than previously appreciated. These results highlight the need for better characterization of gastric mucosal histology in these gastrointestinal disorders.

Effects of Dexlansoprazole MR, a Novel Dual Delayed Release Formulation of a Proton Pump Inhibitor, on Plasma Gastrin Levels in Healthy Subjects

Dexlansoprazole MR is a modified release formulation of a proton pump inhibitor being developed for the treatment of acid‐related disorders. The purpose of this study is to characterize the plasma gastrin (PG) profile associated with administration of dexlansoprazole MR. Forty‐two healthy subjects receive dexlansoprazole MR 90 mg, dexlansoprazole MR 120 mg, and lansoprazole 30 mg once daily for 5 days in a randomized, open‐label, 3‐period crossover study with at least 14‐day washout intervals. Twenty‐four‐hour PG profiles are obtained at baseline (day – 1 of period 1) and on days 1 and 5 in each period. Fasting PG levels are determined on days 8 and 12 in periods 1 and 2. On day 1, 24‐hour PG levels increase from baseline to a similar extent with all regimens. On day 5, 24‐hour PG levels with both dexlansoprazole MR regimens increase further and to a similar extent and are slightly higher than PG levels with lansoprazole. For all regimens, fasting PG levels on days 5 and 6 are higher than baseline levels (P < .05) and start to decrease by day 8, returning to near baseline at day 12. In this study, dexlansoprazole MR administration results in moderate increases in PG, similar to lansoprazole, which return to baseline levels within 7 days post dosing.

Changes of gastric histology in patients with erosive oesophagitis receiving long-term lansoprazole maintenance therapy.

Aliment Pharmacol Ther 2010; 32: 83–96

The 12‐month safety profile of dexlansoprazole, a proton pump inhibitor with a dual delayed release formulation, in patients with gastro‐oesophageal reflux disease

Aliment Pharmacol Ther 2011; 33: 366–377

Long-Term Quality of Life Improvement in Subjects with Healed Erosive Esophagitis: Treatment with Lansoprazole

BackgroundGastroesophageal reflux disease (GERD) is a chronic symptomatic condition and may be associated with erosive esophagitis (EE). Considerable data on the long-term maintenance of healing of EE are available, but data on long-term GERD symptom prevention and patient quality of life (QOL) are limited.AimsTo investigate QOL in subjects with healed EE who received 12 months of double-blind maintenance treatment with lansoprazole or ranitidine, followed by long-term open-label lansoprazole therapy to prevent recurrence of EE.MethodsSubjects with healed EE received 12 months of double-blind maintenance treatment with lansoprazole 15 mg once daily or ranitidine 150 mg twice daily, followed by dose-titrated, open-label lansoprazole therapy for up to 82 months.ResultsDuring double-blind treatment (n = 206), lansoprazole-treated patients showed significantly (P ≤ 0.05) greater improvements than ranitidine-treated patients in the frequency, severity, and ‘bothersomeness’ of heartburn, the symptom index, problems of activity limitation, eating and drinking problems, symptom problems, health distress, and social functioning. During dose-titrated, open-label treatment (n = 195), all disease-specific QOL scales except sleep improved significantly (P < 0.001) from open-label baseline at each time-point.ConclusionsMaintenance treatment with lansoprazole for 12 months in healed EE subjects produced significantly greater improvements in QOL indicators than ranitidine. These improvements were sustained during dose-titrated, open-label lansoprazole treatment.