Speaking at the launch, David Broomfield, Business Unit Manager: Pain, Gastroenterology and Biologics at Adcock Ingram, described dexlansoprazole MR as an exciting new generation PPI. Dexlansoprazole MR is the first new molecule developed for the treatment of GERD in more than 20 years. This exciting new addition to the GERD armamentarium will be costed at 32% below the price of esomeprazole, he announced.

Dexlansoprazole MR is the first new molecule developed for the treatment of gastroesophageal reflux disease in more than 20 years.

State of the art diagnosis and treatment of GERD

In primary care, GERD is treated empirically. Patients are prescribed a PPI and the diagnosis of GERD is based on whether or not the patient responds to treatment. The problem with this type of approach is that heartburn is not specific to GERD but associated with several other diseases, cautioned Prof Fass.

To address this gap, a group of international experts gathered in Lyon (France) in 2018 to develop a definitive diagnostic matrix for GERD. According to Prof Fass, the Lyon Consensus forms the basis of gastroenterology guidelines worldwide. The aim of the Lyon Consensus was to evaluate GERD diagnostic tests and developed criteria which can be used for a definitive diagnosis.1

Conclusive evidence for reflux on oesophageal testing includes advanced grade erosive oesophagitis (Los Angeles grades C and D [see Table 1]), long-segment Barrett’s mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring.1 Prof Fass noted that Los Angeles grade B erosive oesophagitis has been omitted in the current consensus statement but will be included in the update consensus criteria for GERD.

According to the Lyon Consensus, a normal endoscopy does not exclude GERD but rather provides supportive evidence refuting GERD in conjunction with distal AET <4% and <40 reflux episodes on pH-impedance monitoring off PPIs.1

Reflux-symptom association on ambulatory reflux monitoring provides supportive evidence for reflux triggered symptoms and may predict a better treatment outcome when present.1

When endoscopy and pH or pH-impedance monitoring are inconclusive, adjunctive evidence from biopsy findings (histopathology scores, dilated intercellular spaces), motor evaluation (hypotensive lower oesophageal sphincter, hiatus hernia and oesophageal body hypomotility on high-resolution manometry) and novel impedance metrics (baseline impedance, post-reflux swallow-induced peristaltic wave index) can add confidence for a GERD diagnosis.1

However, cautioned the authors of the Lyon Consensus, diagnosis cannot be based on these findings alone. An assessment of anatomy, motor function, reflux burden and symptomatic phenotype will help direct management.1

Phenotypes of GERD patients

Phenotyping will allow clinicians to target and individualise treatment of GERD patients. The overall aim of phenotyping is to gain a better understanding of the patient in front of you, to determine whether he/she has GERD, and what type of GERD he/she may have, noted Prof Fass.

If you have a patient with heartburn, but are not sure about the diagnosis, try to figure out if they fall into any of the below major phenotypes. It is important to phenotype as each require a different therapeutic approach, he added.

Major GERD phenotypes are:3

  1. Non-erosive reflux disease
  2. Reflux hypersensitivity
  3. Functional heartburn
  4. Low grade oesophagitis
  5. High grade oesophagitis
  6. Barrett’s oesophagus
  7. Regurgitation predominant
  8. Chest pain
  9. Laryngitis extra-oesophageal.

However, Prof Fass does not consider all the above phenotypes such as reflux hypersensitivity and functional heartburn, as GERD. Rather, he views them as functional oesophageal disorders, which require a different therapeutic approach.

Refractory GERD

Another important aim of phenotyping is to reduce the percentage of patients who may advance to refractory GERD. Refractory GERD can affect up to 40% of patients who use a PPI. Refractory GERD patients are those who fail to improve on twice a day PPI treatment for at least three months, he clarified.

Nine groups of refractory GERD phenotypes have been proposed:4

  1. Breakthrough acid with large hiatal hernia
  2. Breakthrough acid with small/absent hiatal hernia
  3. Reflux hypersensitivity to heartburn with large hiatal hernia
  4. Reflux hypersensitivity to regurgitation with large hiatal hernia
  5. Reflux hypersensitivity to heartburn with small/absent hernia
  6. Reflux hypersensitivity to regurgitation with small/absent hiatal hernia
  7. Elevated reflux burden with large hiatal hernia
  8. Elevated reflux burden with small/absent hiatal hernia
  9. Negative testing.

In his practice, most patients with refractory GERD fall into category number nine.

What is unique about dexlansoprazole MR?

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.  The history of dexlansoprazole MR starts with lansoprazole, a mixture of R- and S-lansoprazole.

Although R- and S-enantiomers have the same chemical structure, most enantiomers of racemic drugs exhibit marked differences in biological activities such as metabolism, noted Prof Fass.

Dexlansoprazole is the 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.5,6

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.7

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.7,8

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.7

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.

The effect of dexlansoprazole MR on night-time GERD symptoms and sleep disturbances

Nocturnal heartburn and related sleep disturbances are common among patients with GERD. Fass et al evaluated the efficacy of dexlansoprazole MR 30mg in relieving nocturnal heartburn and GERD-related sleep disturbances, improving work productivity, and decreasing nocturnal symptom severity in patients with symptomatic GERD.9

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.9

The primary endpoint was the percentage of nights without heartburn. Secondary endpoints were the percentage of patients with relief of nocturnal heartburn and of GERD-related sleep disturbances over the last seven days of treatment.9

Dexlansoprazole MR 30mg was superior to placebo in median percentage of nights without heartburn (73.1% vs 35.7%, respectively). Dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of nocturnal heartburn and GERD-related sleep disturbances (47.5% vs 19.6%, 69.7% vs 47.9%, respectively), and led to significantly greater improvements in sleep quality and work productivity and decreased nocturnal symptom severity.9

Stepping down with dexlansoprazole MR

Many patients with GERD 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.10

Fass et al investigated whether step-down to once-daily dexlansoprazole MR controls heartburn in patients with GERD who were receiving twice-daily PPI therapy. Patients taking a twice-daily PPI for symptom control were enrolled (n=178) in a single-blind, multicentre study (163 completed the study and 142 patients met criteria for the efficacy analysis).10

During the six-week screening and treatment periods, patients recorded the presence of heartburn symptoms twice daily in electronic diaries. Patients’ heartburn was considered well controlled if they had an average of one symptom or fewer per week during the last four weeks of screening and treatment.10

After screening, qualified patients were switched to masked dexlansoprazole MR 30mg and placebo for six weeks. The primary efficacy endpoint was the proportion of patients whose heartburn remained well controlled after step-down.10

After step-down to once daily dexlansoprazole MR 30mg, heartburn remained well controlled in 88% of patients. These patients were able to maintain their GERD-related symptom severity and QOL.10

Fass et al concluded that most patients with GERD who take twice-daily PPI to control heartburn can successfully step down to once-daily dexlansoprazole 30mg.10

Does food affect dexlansoprazole MR?

Several studies have revealed that food may significantly affect the pharmacokinetic parameters of PPIs. Lee et al evaluated the effect of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR following oral administration. This was an open-label, single-dose, randomised, four-way crossover study involving healthy participants (n=48). Participants received placebo (day one) and dexlansoprazole MR 90mg (day three) after fasting, five or 30 minutes before a high-fat breakfast, or 30 min after a high-fat breakfast.11

Intragastric pH (days one and three) and pharmacokinetics (day three) of dexlansoprazole MR were assessed over a 24-hour interval after each dose. Following administration of dexlansoprazole MR under fasted/fed conditions, mean dexlansoprazole plasma concentration-time profiles generally exhibited two distinct peaks, resulting from the DDR formulation.11

Increases in dexlansoprazole maximum plasma concentration (12%-31%) and area under the plasma concentration-time curve (9%-21%) were observed with the fed regimens. However, differences in intragastric pH were not considered clinically relevant. Dexlansoprazole MR can be administered without regard to food or the timing of food in most patients, concluded the authors.11

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 of dexlansoprazole MR

A randomised, multicentre, placebo-controlled, double-blind crossover study was conducted in patients diagnosed with symptomatic, endoscopically confirmed non-erosive GERD. During the four-week trial, patients who received 30mg dexlansoprazole MR had significantly more symptom free 24-hour periods than patients who received placebo.7,8

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%).7,8

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.7,8

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.7,8

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.7,8

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.7,8

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%).7,8

How is dexlansoprazole MR 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.7

Dexlansoprazole MR is pregnancy category B (there are no adequate and well-controlled studies with dexlansoprazole in pregnant women).7

REFERENCES:

  1. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut, 2018.
  2. Sami SS and Ragunath K. The Los Angeles Classification of Gastroesophageal Reflux Disease. Video Journal and Encyclopedia of GI Endoscopy, 2013.
  3. Katzka DA, Kahrilas PJ. Advances in the diagnosis and management of gastroesophageal reflux disease. BMJ. 2020.
  4. Yadlapati R, Vaezi MF, Vela MF, et al. Management Options for Patients With GERD and Persistent Symptoms on Proton Pump Inhibitors: Recommendations From an Expert Panel. American Journal of Gastroenterology, 2018.
  5. Behm BW, Peura DA. Dexlansoprazole MR for the management of gastroesophageal reflux disease. Expert Rev Gastroenterol Hepatol, 2011.
  6. Katsuki H, Yagi H, Arimori K, et al. Determination of R(+)- and S(−)-lan-soprazole using chiral stationary-phase liquid chromatography and their enantioselective pharmacokinetics in humans. Pharm Res, 1996.
  7. Dexilant® (dexlansoprazole) delayed release capsules [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2011.
  8. Data on file. Takeda Pharmaceuticals USA, Inc.
  9. Fass R, Johnson DA, Orr WC, et al. The effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD. Am J Gastroenterol, 2011.
  10. Fass R, Inadomi J, Han C, et al. Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release. Clin Gastroenterol Hepatol, 2012.
  11. Lee R, Vakily M, Mulford D et al. Clinical trial: The effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel Dual Delayed Release formulation of a proton pump inhibitor – Evidence for dosing flexibility. Alimentary Pharmacology and Therapeutics, 2009.