An in-depth look at the comparative pharmacodynamics of Dexlansoprazole and Esomeprazole for the management of gastroesophageal reflux disease (GORD).

Dexlansoprazole and esomeprazole, both belonging to the proton pump inhibitor class, are pivotal in managing acid-related gastrointestinal disorders (GORD). However, incomplete acid suppression remains a challenge with once-daily dosing.

Proton pump inhibitors (PPIs) are cornerstone therapies for various acid-related gastrointestinal conditions. However, challenges persist, including incomplete acid suppression and delayed onset of action with once-daily dosing.

GORD definition

The definition of GORD has been an evolving one. Initially felt to be synonymous with tissue damage, it has been recognised that many patients with GORD experience a strong symptom-based component (including heartburn and regurgitation) in the absence of endoscopic and histologic evidence of injury.

With the rise in prevalence of reflux disease, as well as varying manifestations of the disorder, a concise definition was felt to be necessary both to define the problem and to address management recommendations for patients and providers. In 2006, the Montreal consensus defined GORD as, “A condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.” Using this unifying definition, treatment for patients with GORD should focus on management of both complications from reflux and significant symptoms relative to the disorder.

Pharmacology and formulation: Dexlansoprazole and esomeprazole inhibit the (H+,K+)-ATPase enzyme, thereby suppressing gastric acid secretion and elevating intragastric pH. Dexlansoprazole modified-release employs a dual delayed-release (DDR) system, ensuring drug release at proximal and distal small intestine segments, leading to distinct plasma concentration-time profiles. Initial drug release in the proximal small intestine is followed by subsequent release in distal regions several hours later. Conversely, esomeprazole's delayed-release formulation achieves peak plasma concentrations approximately 1.6 hours post dose, necessitating ingestion before meals for optimal efficacy.

Unfortunately, many patients continue to suffer from symptoms related to GORD despite appropriate use of PPIs. Dexlansoprazol MR addresses limitations with short plasma half-life and need for meal-associated dosing, characteristic of conventional PPIs. In addition, it has been shown to be effective in several specific clinical situations. These include:

• Coadministration with clopidogrel
• Healing of all grades of erosive esophagitis
• Improvement in reflux-related quality of life
• Step down to once-per-day dosing
• Induces symptom improvement in patients with:
  • Nonerosive oesophageal reflux disease
  • Nocturnal heartburn
  • GORD-related sleep disturbance
  • Regurgitation.

Dexlansoprazole dual delayed-release technology releases drug in two phases:

• Release 1: Granule 1 comprises 25% of total dose and is released at pH5.5 within 1-2 hours of dosing.
• Release 2: Granule 2 comprises 75% of total dose and is released at pH6.75 4-5 hours after dosing.

The formulation of dexlansoprazole utilising dual delayed release technology results in a dexlansoprazole plasma concentration-time profile with two distinct peaks. The first peak occurs one to two hours after administration, followed by a second peak within four to five hours. Dexlansoprazole can be taken without regard to food or the timing of food.

Comparator pH study: single-dose pharmacodynamics of dual delayed-release dexlansoprazole 60mg vs delayed-release esomeprazole 40mg

Kukulka et al compared the pharmacodynamic effects of dexlansoprazole modified release and esomeprazole, utilising doses approved for erosive esophagitis healing. Intragastric pH measurement serves as a reliable indicator of PPI efficacy. This study assessed the pharmacodynamic effects of single doses of dexlansoprazole modified-release 60mg and esomeprazole 40mg on 24-hour intragastric pH in healthy subjects.

Study design and methodology: The study employed a randomised, crossover design, with each subject serving as their control. Dosage strengths chosen mirror those approved for healing erosive esophagitis. Intragastric pH measurement serves as a reliable indicator of PPI efficacy, allowing for a head-to-head comparison of dexlansoprazole modified release
and esomeprazole.

Results: Dexlansoprazole modified-release exhibits prolonged gastric acid control compared to esomeprazole, especially evident in the 12-24-hour post dose interval. The percentage of time with intragastric pH >4 over 24 hours significantly favours dexlansoprazole. Dexlansoprazole exhibits significantly greater pH control over 24 hours, with dual-peaked pharmacokinetics enhancing its efficacy.

While both drugs show comparable pharmacodynamic activity in the initial 0-12 hours post dose, dexlansoprazole's extended duration of action underscores its clinical advantage. The study's crossover design enhances reliability, although its single-dose nature limits extrapolation to multiple-dose regimens.

While clinical efficacy assessment in healthy volunteers is constrained, the study highlights the pharmacological implications of PPI formulation characteristics. Dexlansoprazole modified-release demonstrates extended gastric acid control compared to esomeprazole, particularly evident in the 12-24-hour post dose interval.

Conclusion: A single dose of dexlansoprazole modified-release 60mg demonstrates superior gastric acid control over a 24-hour period compared to esomeprazole 40mg.

The extended duration of acid suppression with dexlansoprazole, particularly in the latter half of the post dose interval, underscores its potential clinical advantages. Although both drugs exhibit comparable efficacy within the initial 0-12 hours post dose, dexlansoprazole's dual delayed-release formulation offers promise in optimising acid suppression in acid-related gastrointestinal disorders.

This highlights its potential in optimising acid suppression. While limitations in the study design preclude extrapolation to multiple-dose regimens, the comparison underscores the pharmacological significance of PPI formulation characteristics. Dexlansoprazole's dual delayed-release formulation exhibits extended gastric acid control compared to esomeprazole, offering potential advantages in clinical practice.

References:

Frye JW, Peura DA. Managing gastroesophageal reflux disease - comparative efficacy and outcomes of dexlansoprazole MR. Ther Clin Risk Manag. 2015:30;11:1649-56. doi: 10.2147/TCRM.S66680. PMID: 26586949; PMCID: PMC4634831.

Metz DC, Howden CW, Perez MC, Larsen L, O'Neil J, Atkinson SN. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther. 2009:1;29(7):742-54. doi: 10.1111/j.1365-2036.2009.03954.x. Epub 2009 Feb 7. PMID: 19210298.

Howden CW, Larsen LM, Perez MC, Palmer R, Atkinson SN. Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis - maintenance of healing and symptom relief. Aliment Pharmacol Ther. 2009:1;30(9):895-907. doi: 10.1111/j.1365-2036.2009.04119.x. Epub 2009 Aug 14. PMID: 19681809.

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. Epub 2011 Sep 14. Erratum in: Clin Exp Gastroenterol. 2011;4:255. PMID: 22016582; PMCID: PMC3190289.