Dexlansoprazole MR is the first new molecule developed for the treatment of GORD in more than 20 years. PPIs are rapidly absorbed and subsequently eliminated, leading to a short plasma half-life. The effects of PPIs tend to diminish during the 24-hour period enabling resumption of gastric acid secretion by uninhibited, restored, or new proton pumps towards the end of the 24-hour dosing interval (if given once daily). The majority of PPIs releases a high serum level 60 to 90 minutes after administration with less than 25% available four hours post-dose and less than 5% eight hours post-dose, explained Prof Fass.

What makes dexlansoprazole MR unique is that unlike other PPIs, which have a delayed release, the new agent has a dual-delayed release formulation. Dexlansoprazole is a R-enantiomer, which is associated with three to five times greater maximum concentration, area under the plasma concentration–time curve, and time to maximum concentration values than the S-enantiomer, and smaller total body clearance values, so it has greater systemic exposure than lansoprazole and a longer elimination half-life than S-lansoprazole.

Dexlansoprazole MR is available in capsule format, which contains a dual-delayed release formulation that provides two releases of the drug – a major differentiating feature. The once-daily capsules contain two types of enteric-coated granules, and each has a different pH-dependent release. Granule 1 releases ~25% of the dose at a pH ≥5.5 in the proximal part of the duodenum. Granule 2 releases ~75% of the dose at a pH ≥6.75 in the distal part of the ileum, creating a unique pharmacokinetic pattern. There is about a four-hour difference between the first and second release. This results in a plasma concentration-time profile with two distinct peaks.

The initial peak in plasma concentration occurs about an hour or two after dexlansoprazole MR is taken. The second peak occurs about four to five hours after initial dosing. This creates an important effect on the drug level in the serum because the effective level in the serum stays over a longer period compared to other PPIs, stressed Prof Fass.

Night-time GORD symptoms and sleep disturbances

Nocturnal heartburn and related sleep disturbances are common among patients with GORD. Fass et al evaluated the efficacy of dexlansoprazole MR 30mg in relieving nocturnal heartburn and GORD-related sleep disturbances, improving work productivity, and decreasing nocturnal symptom severity in patients with symptomatic GORD.

Patients with frequent, moderate-to-very-severe, nocturnal heartburn and associated sleep disturbances were randomised 1:1 in a double-blind fashion to receive dexlansoprazole MR (n=152) or placebo (n=153) once daily for four weeks.

The primary endpoint was the percentage of nights without heartburn. Secondary endpoints were the percentage of patients with relief of nocturnal heartburn and of GORD-related sleep disturbances over the last seven days of treatment. Dexlansoprazole MR 30mg was superior to placebo in median percentage of nights without heartburn (73% vs 35%, respectively). Dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of nocturnal heartburn and GORD-related sleep disturbances (47% vs 19%, 69% vs 47%, respectively), and led to significantly greater improvements in sleep quality and work productivity and decreased nocturnal symptom severity.

Stepping down with dexlansoprazole MR

Many patients with GORD take a PPI twice daily to control symptoms. Because of dexlansoprazole MR’s dual-delayed release formulation, it can be dosed once-daily, making it an attractive option for step-down management of patients whose symptoms are well controlled on twice-daily PPIs.

Does food affect dexlansoprazole MR?

Several studies have revealed that food may significantly affect the pharmacokinetic parameters of PPIs. While dexlansoprazole MR can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions, said Prof Fass.

Safety and tolerability

A randomised, multicentre, placebo-controlled, double-blind crossover study was conducted in patients diagnosed with symptomatic, endoscopically confirmed non-erosive GORD. During the four-week trial, patients who received 30mg dexlansoprazole MR had significantly more symptom free 24-hour periods than patients who received placebo.

In addition, more patients who received dexlansoprazole MR 30mg experienced 24-hour relief as early as the first three days of treatment (on day three dexlansoprazole MR 38% vs placebo 15%), and this pattern was sustained throughout the treatment period (on day 28, dexlansoprazole 63% vs placebo 40%).

The efficacy of dexlansoprazole MR for healing of erosive oesophagitis (EE) was evaluated in two randomised, multicentre, controlled studies that included more than 1 300 patients each with endoscopically confirmed EE.

In patients with at least one post-baseline endoscopy, dexlansoprazole MR provided effective healing of EE in 70% and 66% of patients after four weeks, and in 87% and 85% of patients after eight weeks (the primary efficacy endpoint) of treatment in the respective studies.

Finally, the efficacy of dexlansoprazole MR for maintaining healing of EE was evaluated in patients who had successfully completed a phase III clinical trial of EE and had endoscopically confirmed healing of EE.

In a randomised, placebo-controlled, double-blind, six-month clinical trial, patients received 30mg dexlansoprazole MR (n=125) or placebo (n=119). Based on crude-rate analysis, 66% of patients who received dexlansoprazole MR had maintained healing of their oesophageal erosions for six months, compared with 14% of those receiving placebo who were still healed.

Most reported treatment-emergent adverse reactions: diarrhoea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

How is it prescribed?

Dexlansoprazole MR is available as 30mg or 60mg capsules approved for once-daily, oral administration in adult patients. Once-daily dexlansoprazole MR 60mg is indicated for healing all grades of EE for up to eight weeks and the 30mg is indicated for treatment of heartburn associated with symptomatic non-erosive reflux disease for up to four weeks, as well as the maintenance of healed EE and heartburn relief for up to six months.

Dexlansoprazole MR is pregnancy category B (there are no adequate and well-controlled studies with dexlansoprazole in pregnant women).

REFERENCES:

Bosman, R. Finally a breakthrough treatment for GERD – it’s taken 20 years! Specialist Forum July 2022. Vol.22, No.7.