Comparison of Pharmacodynamics between Tegoprazan and Dexlansoprazole Regarding Nocturnal Acid Breakthrough: A Randomized Crossover Study.

Background/Aims: Tegoprazan, a novel potassium-competitive acid blocker, is expected to overcome the limitations of proton pump inhibitors and effectively control nocturnal acid breakthrough. To evaluate the pharmacodynamics of tegoprazan versus dexlansoprazole regarding nocturnal acid breakthrough in healthy subjects. Methods: In a randomized, open-label, single-dose, balanced incomplete block crossover study, 24 healthy male volunteers were enrolled and randomized to receive oral tegoprazan (50, 100, or 200 mg) or dexlansoprazole (60 mg) during each of two administration periods, separated by a 7- to 10-day washout period. Blood samples were collected for pharmacokinetic parameter analysis; gastric monitoring was performed for pharmacodynamic parameter evaluation. Results: All 24 subjects completed the study. Average maximum plasma concentration, area under the plasma concentration-time curve, and mean time with gastric pH >4 and pH >6 for tegoprazan demonstrated dose-dependent incremental increases. All the tegoprazan groups reached mean pH ≥4 within 2 hours, whereas the dexlansoprazole group required 7 hours after drug administration. Based on pharmacodynamic parameters up to 12 hours after evening dosing, 50, 100, and 200 mg of tegoprazan presented a stronger acid-suppressive effect than 60 mg of dexlansoprazole. Moreover, the dexlansoprazole group presented a comparable acid-suppressive effect with the tegoprazan groups 12 hours after dosing. Conclusions: All the tegoprazan groups demonstrated a significantly faster onset of gastric pH increase and longer holding times above pH >4 and pH >6 up to 12 hours after evening dosing than the dexlansoprazole group.

Development of Dexlansoprazole Delayed-Release Capsules, a Dual Delayed-Release Proton Pump Inhibitor.

Proton pump inhibitors (PPIs) are widely used for treating acid-related disorders. For an "ideal PPI," achieving maximal absorption and sustaining pharmacodynamic effects through the 24-h dosing cycle are critical features. Dexlansoprazole offers a relevant case study on how an improved PPI was developed capitalizing on the rational optimization of a precursor molecule-in this case, using lansoprazole as a starting point, leveraging its chemical properties on pharmacokinetics, and exploring optimized formulations. Dexlansoprazole is the R(+)-enantiomer of lansoprazole and shows stereoselective differences in absorption and metabolism compared with the racemic mixture of lansoprazole. The formulation was further refined to use pulsate-type granules with enteric coating to withstand acidic gastric conditions, while allowing prolonged absorption in the proximal and distal small intestine. As a result, the dual delayed-release formulation of dexlansoprazole has a plasma concentration-time profile characterized by 2 distinct peaks, leading to an extended duration of therapeutic plasma drug concentrations compared with the conventional delayed-release lansoprazole formulation. The dual delayed-release formulation maintains plasma drug concentrations longer than the lansoprazole delayed-release formulation at all doses.

Pharmacokinetic/Pharmacodynamic Evaluation of Dexlansoprazole Infusion Injection Compared with Lansoprazole in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: This study was performed in healthy Chinese subjects to evaluate the safety and pharmacokinetic/pharmacodynamic characteristics of a novel injection formulation of dexlansoprazole in the context of single and multiple administration, compared with the original lansoprazole injection. METHODS: Helicobacter pylori-negative healthy volunteers were recruited, and 70 participants were enrolled into five dosing groups (seven males and seven females in each group), including 15 mg once daily (qd), 15 mg every 12 h (q12h), 30 mg qd and 30 mg q12h of dexlansoprazole treatment for 5 days, as well as 30 mg q12h of lansoprazole treatment for 5 days. Blood samples were collected at scheduled time spots postdose on day 1 (first dose) and day 5 (last dose). Twenty-four-hour intragastric pH was continuously monitored on day 0 (baseline) and days 1 and 5. Dexlansoprazole and S-lansoprazole in human plasma were determined by validated chiral liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were determined by a non-compartmental method using Phoenix WinNonlin software. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events. RESULTS: The half-life (t½) and clearance (CL) of dexlansoprazole were 1.76-2.06 h and 4.52-5.40 L/h, respectively, while the t½ and CL of S-lansoprazole were 0.87-1.02 h and 34.66-35.98 L/h, respectively. No drug accumulation after repeated administration was noted. Administration of lansoprazole 30 mg resulted in higher area under the concentration-time curve from time zero to the last measurable concentration (AUCt) of dexlansoprazole than that of dexlansoprazole 15 mg (p = 0.026). Zero to 24 h after q12h multiple dosing, median and mean intragastric pH, percentage of time with the intragastric pH above 4.0 [TpH ≥ 4.0(%)] and percentage of time with the intragastric pH above 6.0 [TpH ≥ 6.0(%)] in the dexlansoprazole 15 mg q12h group were 6.07 ± 0.61, 5.70 ± 0.76, 83.58 ± 12.34, and 53.70 ± 17.06, respectively, which was similar to the lansoprazole 30 mg q12h group, i.e. 6.15 ± 0.62, 5.88 ± 0.67, 87.26 ± 12.08 and 57.00 ± 16.35, respectively. A weak positive correlation between dexlansoprazole AUCt and baseline-adjusted TpH ≥ 4.0(%) over 0-24 h was observed, with Pearson correlation coefficients of 0.437 (p = 0.029), while no correlation was observed between AUCt and baseline-adjusted TpH ≥ 6.0(%) over 0-24 h. CONCLUSION: Every 12 h intravenous dosing of dexlansoprazole up to 30 mg for 5 days was safe and well-tolerated in healthy Chinese subjects. Every 12 h dosing of dexlansoprazole 15 mg has a comparable effect of gastric acid inhibition as lansoprazole 30 mg q12h. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03120273.

Safety, tolerability, pharmacokinetics and pharmacodynamics of dexlansoprazole injection in healthy Chinese subjects.

PURPOSE: This study was conducted to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of dexlansoprazole injection in healthy subjects. METHODS: Dexlansoprazole (20-90 mg) or lansoprazole (30 mg) was administrated intravenously to healthy male and female volunteers. All the subjects were sampled for pharmacokinetic (PK) analysis and 64 of them were monitored for 24-h intragastric pH prior to and after administration in the pharmacodynamic (PD) study. RESULTS: Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-τ) for dexlansoprazole injection was dose-proportional over the range of 20-90 mg following a single intravenous administration. Total clearance and half-life (t1/2) was independent of dose, and ranged from 4.69 L/h to 5.85 L/h and from 1.24 h to 2.17 h, respectively. A single dose of dexlansoprazole (30 mg) resulted in higher gastric pH compared to that of lansoprazole, evidenced by a mean 24-h gastric pH of 6.1 ± 1.2 (lansoprazole: 5.4 ± 1.1) and 24-h gastric pH > 6 post drug dose holding time of 64.2 ± 21.0% (lansoprazole: 49.5 ± 21.5%). CONCLUSION: Dexlansoprazole injection was safe and well tolerated for up to 5-day repeated intravenous administration dose of 30 mg. The recommended dosage for dexlansoprazole injection is 30 mg for an adequate gastric acid control.

Treatment of gastroesophageal reflux disease: two new oral formulations dexlansoprazole MR and esomezol (esomeprazole strontium).

INTRODUCTION: The prevalence of gastroesophageal reflux disease continues to increase with the aging population and the obesity epidemic. Therapeutic failures can have significant detrimental effects in patients. Recently, dexlansoprazole MR and esomeprazole strontium were introduced to the class of proton pump inhibitors (PPIs). AREAS COVERED: This article will review the pharmacodynamics and pharmacokinetics of dexlansoprazole MR and esomeprazole strontium. Using the keywords 'dexlansoprazole MR' and 'esomeprazole strontium' in the search engines of PubMed, Cochrane Reviews and Google, we were able to identify peer-reviewed publications, abstracts and presentations at national society educations meetings and present a balanced view of the available data. EXPERT OPINION: Dexlansoprazole MR and esomeprazole strontium offer an innovative delivery mechanism compared to conventional PPIs. Further trials are necessary in order to establish superiority.