The PPI, introduced in 1989, reflected a major medical therapeutic breakthrough in the treatment of peptic ulcers and GORD, resulting in more rapid healing of the lesions and symptom relief. A PPI is a prodrug which is activated by acid.3
PPIs have about one hour of elimination half-life. The area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Omeprazole was the first PPI introduced into the market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different.4
Dexlansoprazole has shown the best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.4
Because PPIs have a relatively short half-life and not all pumps are activated, it takes about three days to reach steady state inhibition of acid secretion as a balance is struck between covalent inhibition of active pump, subsequent stimulation of inactive pumps after the drug has been eliminated from the blood and de novo synthesis of new pumps. The target for treatment of many acid-related disorders is reduction of gastric acid secretion. PPIs are widely used to reduce acid secretion in patients with GORD.1,4
While PPIs are widely regarded as the gold-standard of GORD treatment, there are several clinical limitations to some PPIs. PPIs are associated with limited ability to fully relieve the discomfort of GORD, particularly at night. Studies show that only 23% of patients felt that their pain and discomfort was completely controlled with PPIs at night and 94% continued to experience breakthrough symptoms.1
This resulted in 49% of respondents using adjunctive medications to control discomfort. An estimated 45% of respondents found that treatment for nocturnal pain was unsatisfactory. Approximately 38% of patients taking PPIs had breakthrough symptoms, and an overwhelming 65% of these patients experienced them at night.1
According to Goh et al, the active ingredient in a PPI must be present in high concentrations when the proton pumps are stimulated before and during a meal. As PPIs are acid labile, they need protection from degradation in the stomach by enteric coating or buffering. PPIs are rapidly absorbed and subsequently eliminated, leading to a short plasma half-life and ultimately restricting their administration to before meals to achieve their full effect.1
As pre-meal dosing is not always convenient, this may lead to poor adherence. However, participants reported good adherence to the prescribed therapies in terms of frequency of administration (87%), timing of medication (87%), and mealtimes (88%).1
Dexlansoprazole is the R-enantiomer of the PPI lansoprazole, a racemic mixture of R-lansoprazole and S-lansoprazole. The R-enantiomer is associated with three to five times times greater maximum concentration (Cmax), 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.1
Dexlansoprazole is the first PPI with a dual delayed release formulation designed to provide two separate releases of medication to extend the duration of effective plasma drug concentration. Dexlansoprazole has been shown to be effective for healing of erosive oesophagitis, and to improve patient well-being by controlling 24 hour symptoms.1
Dexlansoprazole has also been shown to achieve good plasma concentration, regardless of administration with or without food, providing flexible dosing. The dual delayed release formulation of dexlansoprazole results in a plasma concentration-time profile with two peaks.1
The pharmacodynamic impact of the second peak is that PPIs work only on activated H+, K+-ATPase enzyme (proton pumps), of which 70%-80% are activated after a meal, leaving 20%-25% inactivated. These can still be activated and lead to acid secretion. Additionally, these proton pumps have a half-life of about 50 hours, meaning that about 25% of the pumps are produced daily at about 1% per hour. These newly produced H+, K+-ATPase enzyme (proton pump) can then also produce acid.1
Dual delayed release formulation
The dual delayed release technology in dexlansoprazole uses two types of enteric-coated granules with different pH-dependent dissolution profiles to provide an initial drug release in the proximal small intestine, at a pH of about 5.5, followed several hours later by another drug release at more distal regions of the small intestine, at a pH of ≥6.75.1
Dexlansoprazole therefore produces a dual-peaked pharmacokinetic profile, as opposed to the single peak seen with conventional PPIs. Dexlansoprazole increases the mean intragastric pH and the duration that intragastric pH is >4 over a 24 hour period. The optimal dose range is 30-90mg, and the two doses currently approved for clinical use are 30mg and 60mg.1
Dexlansoprazole is the first PPI with a dual delayed release formulation designed to provide two separate releases of medication. In January 2009, the American Food and Drug Administration approved dexlansoprazole for the treatment of heartburn associated with symptomatic non-erosive GORD, healing of erosive oesophagitis and maintenance of healed erosive oesophagitis at doses of 30mg and 60mg once daily.1
Frye et al (2015) explain that the R-enantiomer is subsequently associated with decreased clearance compared to the S-enantiomer. However this is not the sole mechanism that extends the effect of dexlansoprazole modified release (MR), as the elimination half-life of dexlansoprazole is like other PPIs (about one to two hours). It is the delivery system, rather than the inherently slower hepatic clearance, that prolongs the plasma residence time of dexlansoprazole MR. The dual delayed-release technology incorporates two distinct sets of enteric-coated granules that are designed to offer two distinct, pH-dependent releases of drug.5
The gelatine capsule containing the granules dissolves in the stomach, and the first set of granules (~25% of the drug dose) is released into the proximal duodenum (pH 5.5). This results in an early rise in plasma concentration (one to two hours), similar to other PPIs. The remaining granules (75%) are designed to be released in the distal small intestine (pH 6.75), resulting in a second concentration peak at four to five hours after ingestion. This delivery system provides a prolonged duration of acid suppression and helps to limit the necessity for more than once-daily dosing.5
A randomised, open-label, two-period crossover study compared the pharmacodynamic effects of single-dose dexlansoprazole MR 60mg and esomeprazole 40mg on 24 hour intragastric pH in healthy adult subjects showed the average 24 hour intragastric pH following a single dose of dexlansoprazole MR was higher compared to a single dose of esomeprazole (58% vs 48%; P=0.0003). The most important difference was noted in the second half of the day, presumably due to the longer duration of action of dexlansoprazole MR.5
Chiang et al (2019) compared the clinical efficacy of single doses of dexlansoprazole (MR 60mg) and esomeprazole (40mg) after 24-weeks follow-up in patients with mild erosive oesophagitis. Patients displaying complete symptom resolution (CSR) by the end of initial treatment (eight weeks) were switched to on-demand therapy until the end of 24 weeks.2
The GERD Questionnaire scores at 4-, 8-, 12-, 16-, 20-, and 24-week posttreatment were less than the baseline score. The CSR, rate of symptom relapse, days to symptom resolution, sustained healing rate of erosive oesophagitis, treatment failure rate, and the number of tablets taken in 24 weeks were similar in both groups. The esomeprazole group had more days with reflux symptoms than the dexlansoprazole group (37.3±37.8 vs 53.9±54.2; P=0.008). In the dexlansoprazole group, patients exhibited persistent improvement in the GERDQ score during the on-demand period (week eight vs week 24; P<0.001) but not in the esomeprazole group (week 8 vs week 24; P=0.846).2
This study suggests that the symptom relief effect for GERD after 24 weeks was similar for dexlansoprazole and esomeprazole. Dexlansoprazole exhibited fewer days with reflux symptoms in the 24 week study period, with better persistent improvement in the GERDQ score in the on-demand period.2
Since PPIs were introduced, considerable progress has been made in the management of acid-related diseases. The average 24 hour intragastric pH following a single dose of dexlansoprazole MR was higher compared to a single dose of esomeprazole (58% vs 48%; P=0.0003). The most important difference was noted in the second half of the day, presumably due to the longer duration of action of dexlansoprazole MR.5
- Goh KL, Choi MG, Hsu PI, et al. Pharmacological and Safety Profile of Dexlansoprazole: A New Proton Pump Inhibitor - Implications for Treatment of Gastroesophageal Reflux Disease in the Asia Pacific Region. J Neurogastroenterol Motil, 2016 Jul 30;22(3):355-66. doi: 10.5056/jnm15150. PMID: 26932927; PMCID: PMC4930293.
- Chiang HH, Wu DC, Hsu PI, et al. Taiwan Acid-Related Disease Study Group. Clinical efficacy of 60-mg dexlansoprazole and 40-mg esomeprazole after 24 weeks for the on-demand treatment of gastroesophageal reflux disease grades A and B: a prospective randomized trial. Drug Des Devel Ther, 2019 Apr 26;13:1347-1356. doi: 10.2147/DDDT.S193559. PMID: 31118571; PMCID: PMC6499145.
- 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.
- Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil, 2013 Jan;19(1):25-35. doi: 10.5056/jnm.2013.19.1.25. Epub 2013 Jan 8. PMID: 23350044; PMCID: PMC3548122.
- 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.