Following a diagnosis of GORD, initial steps in the management involve optimising PPI therapy and ensuring proper administration to enhance adherence to treatment. In cases of persistent symptoms, increasing the PPI dosage to twice daily may be considered for select patients.²

However, it is crucial for primary care providers to investigate the origin of symptom generation, distinguishing between reflux and non-reflux mechanisms, particularly when symptoms do not respond well to optimal PPI therapy, stress Liang et al.²

Effectiveness of PPIs and switching to once-daily dosing

While numerous studies have demonstrated the effectiveness of PPIs in providing relief from symptoms in GORD, up to 40% of patients report a less-than-optimal response to once-daily PPI therapy. For these patients increasing PPI dosage to twice daily may be appropriate.^2,3

 In patients who are successfully managed with twice-daily PPI therapy, step-down therapy to once-daily PPIs may be considered – especially when taking into consideration that the prolonged use of high-dose PPI therapy can increase the risk of osteoporosis-related fractures of the hip and spine, bacterial overgrowth, Clostridium difficile colitis, and community-acquired pneumonia.^2,3

Fass et al investigated whether switching to once-daily dexlansoprazole modified release (MR), a PPI with a dual-delayed release formulation (see box 3), can be used to effectively manage heartburn in patients living with GORD who were initially on twice-daily PPI therapy.³

Effective heartburn control was defined as an average of one symptom or fewer per week during the last four weeks of screening and treatment. Participants were switched to masked dexlansoprazole MR 30mg and placebo for six weeks.³

The primary efficacy endpoint was the proportion of patients maintaining well-controlled heartburn after step-down. Additionally, GORD-related symptoms and quality of life (QoL) were assessed.³

Results indicated that after switching to once daily dexlansoprazole MR 30mg, 88% of patients sustained well-controlled heartburn. The results suggest that a significant majority of patients effectively managed their heartburn by switching from twice-daily PPI therapy to once-daily dexlansoprazole 30mg, demonstrating sustained control over symptoms and maintaining overall QoL related to GORD.³

Comparative efficacy of single doses of dexlansoprazole

In a study conducted by Kukulka et al, the pharmacodynamic effects of single doses of dexlansoprazole MR 60mg and esomeprazole 40mg were compared in healthy adult participants.⁴

Participants were randomised to either dexlansoprazole or esomeprazole. The primary endpoints, covering 24-hours post-dose, included the percentage of time with intragastric pH >4 and mean pH, while secondary endpoints focused on specific time intervals. Both drugs were administered after an overnight fast and one hour before breakfast, with continuous pH recording spanning from pre-dose to 24-hours post-dose.⁴

Results showed that over the entire 24-hour post-dose period, dexlansoprazole demonstrated a statistically significant increase in the mean percentage of time with pH >4 (58% for dexlansoprazole vs 48% for esomeprazole) and average mean pH values (4.3 for dexlansoprazole vs 3.7 for esomeprazole) compared to esomeprazole.⁴

This significant difference was observed in the >12-24-hour post-dose interval. While no statistically significant difference was noted in the 0-12-hour post-dose interval, the authors concluded that dexlansoprazole 60mg achieved higher average intragastric pH levels over 24 hours compared to a single dose of esomeprazole 40mg.

Dexlansoprazole indications and mode of action

In South Africa, dexlansoprazole is indicated for the treatment of adult and adolescent (12- to 17-years) patients living with EO, the maintenance of healed EO, and the maintenance heartburn relief. Recommended treatment duration is six months for adults and four months for adolescent patients. Dexlansoprazole is also indicated for the short-term treatment of heartburn and acid regurgitation associated with symptomatic non-erosive reflux disease adults and adolescents.⁵

The limitations of conventional PPI therapy include mealtime dosing before meals to maximise efficacy (parietal cell proton pumps are activated with meals) and short half-lives. Dexlansoprazole MR has been developed to specifically address these limitations.⁶

Dexlansoprazole MR has a distinctive dual delayed-release mechanism, delivering the drug in two distinct phases. Within the capsule, granules are equipped with coatings designed to dissolve at specific pH levels.⁷

Granules sensitive to pH 5.5 release in the proximal duodenum, while those sensitive to pH 6.8 release in the distal ileum. This innovative technology ensures a targeted and phased release of the medication for optimal therapeutic efficacy.⁷

Consequently, 25% of the drug is released in the proximal duodenum, and the remaining 75% is released in the distal ileum. This dual-phase release results in a distinctive dual-peak time–concentration profile, setting it apart from regular delayed-release PPIs that exhibit a single peak.⁷

Dexlansoprazole MR, administered once a day, extends therapeutic plasma levels over time, allowing sustained inhibition of newly formed or active proton pumps beyond the initial PPI effect. Importantly, the drug's efficacy does not appear to be influenced by meals, as it can be taken before, after, or during a meal with minimal impact on the drug's effect on intragastric pH.⁷

Overall, the pharmacodynamic profile of dexlansoprazole MR is unique and is anticipated to translate into improved clinical efficacy for patients living with GORD, according to Fass and Frazier.⁷

Take-away messages

1. First-line therapy recommendations: Initial GORD management strategies prioritise first-line treatment with a PPI coupled with lifestyle modifications, highlighting the fundamental approach to symptom relief and prevention of complications.
2. Risk mitigation through step-down therapy: Recommending step-down therapy for well-controlled patients on twice-daily PPIs aims to mitigate potential risks associated with prolonged high-dose PPI usage, ensuring a balanced and safe treatment approach.
3. Comprehensive disease management: Dexlansoprazole not only improves GORD symptoms but also plays a crucial role in preventing complications like EO, BO and oesophageal adenocarcinoma, offering a comprehensive approach to disease management.
4. Optimised PPI therapy: Overcoming conventional PPI limitations, dexlansoprazole's dual delayed-release mechanism optimises pharmacokinetics and pharmacodynamics. This innovation prolongs acid suppression, minimising breakthrough symptoms and the need for frequent dosing.
5. Success in step-down therapy: Dexlansoprazole showcases effectiveness in transitioning from twice-daily to once-daily PPI treatment. A significant majority of patients maintain well-controlled heartburn, ensuring prolonged symptom relief and enhanced overall QoL.
6. Comparative pharmacodynamic superiority: In a direct comparison with dexlansoprazole outperformed esomeprazole, achieving higher intragastric pH levels over a 24-hour period. The dual delayed-release technology reinforces dexlansoprazole's unique and superior clinical efficacy in GORD management.
7. Flexibility in administration: Dexlansoprazole's efficacy remains consistent regardless of meal timing, offering patients the convenience of administration before, after, or during meals without compromising its impact on intragastric pH.

 References

1. Antunes C, Aleem A, Curtis SA. Gastroesophageal Reflux Disease. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441938/
2. Liang SW, Wong MW, Yi CH, et al. Current advances in the diagnosis and management of gastroesophageal reflux disease. Tzu Chi Med J, 2022 May 16;34(4):402-408. doi: 10.4103/tcmj.tcmj_323_21. PMID: 36578634; PMCID: PMC9791847.
3. Fass R, Inadomi J, Han C, Mody R, O’Neil J, Perez MC. Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release. Clin Gastroenterol Hepatol, 2012;10(3):247-53. doi: 10.1016/j.cgh.2011.11.021.
4. Kukulka M, Eisenberg C, Nudurupati S. Comparator pH study to evaluate the single-dose pharmacodynamics of dual delayed-release dexlansoprazole 60 mg and delayed-release esomeprazole 40 mg. Clin Exp Gastroenterol, 2011;4:213-20. doi: 10.2147/CEG.S24063.
5. Professional Information. Updated 2023. Accessed on 7 March 2024. [Internet]. Available at: : https://www.medicalacademic.co.za/wp-content/uploads/sites/2/2024/03/Approved-Dexilant-PI-August-2021.pdf
6. Frye JW, Peura DA. Managing gastroesophageal reflux disease - comparative efficacy and outcomes of dexlansoprazole MR. Ther Clin Risk Manag, 2015;11:1649-56. doi: 10.2147/TCRM.S66680.
7. Fass R, Frazier R. The role of dexlansoprazole modified-release in the management of gastroesophageal reflux disease. Therapeutic Advances in Gastroenterology, 2017;10(2):243-251. doi:1177/1756283X16681701