Esomeprazole in the Treatment of Gastroesophageal Reflux Disease

Basic Introduction

Esomeprazole is the latest PPI and was developed as the S-isomer of omeprazole as an attempt to improve its pharmacokinetic properties. Esomeprazole has been reported to have a somewhat higher potency in acid inhibition than other PPIs. Despite some controversy, data from clinical trials and meta-analyses indicate that esomeprazole 40 mg od for up to 8 weeks provided higher rates of healing of erosive GERD and a greater proportion of patients with sustained resolution of heartburn, than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od. Esomeprazole 20 mg od has also been shown to be more effective in maintaining healing of erosive GERD compared with lansoprazole 15 mg od or pantoprazole 20 mg od. However, it is not clear whether these statistically significant differences are of major clinical importance. Esomeprazole 20 mg od is superior to placebo for treatment of non-erosive reflux disease (NERD) but clinical trials have not shown any significant differences in efficacy between esomeprazole 20 mg and omeprazole 20 mg or pantoprazole 20 mg od. Lastly, although esomeprazole treatment in GERD has been reported to result in improvement of health-related quality of life (QoL) indices, no clinical trials have evaluated the possible differential effects of different PPIs on QoL in GERD.

Synthesis of esomeprazole

Take 3.8kg of esomeprazole potassium prepared in Example 7 and add 7L of water (the weight ratio of esomeprazole potassium to water is 1: 1.84), stir and dissolve, add 9L of ethyl acetate (esomeprazole potassium and acetic acid The weight-volume ratio of ethyl ester is 1: 2.37) dissolved, Reduce the temperature to 10-20 ; add glacial acetic acid to adjust the pH to 6.5,After extracting with ethyl acetate and concentrating the organic solvent, Add 3L ethanol (the weight-volume ratio of esomeprazole potassium to ethanol 1: 0.79) to dissolve, Add an ethanol solution containing 0.48kg sodium hydroxide (0.48kg sodium hydroxide dissolved in 5L ethanol), add ether and stir to crystallize, Obtain the crude product of esomeprazole sodium; Esomeprazole sodium crude product 2.7kg, 9L acetone (equivalent to 3.3 times the volume of the crude esomeprazole sodium crude product), suspension and stirring at 5 ° C, and filtering out insoluble materials. Add 30L of ethyl acetate (equivalent to 11.1 times the weight of the crude product of esomeprazole sodium), stir and crystallize overnight. After centrifugation and drying, 2.33 kg of esomeprazole sodium refined product was obtained.[1]

The effects of esomeprazole on gastric acidity

Recently, acid control with esomeprazole has been compared with that of other PPIs in several cross-over studies in either patients with GERD or in healthy individuals. As shown, all studies showed that esomeprazole 40 mg od was more effective in maintaining intragastric pH at 4.0 or lower compared with all other PPIs given at standard doses. The same studies demonstrated that esomeprazole 40 mg od is superior to all other PPIs at standard doses in terms of achieving higher 24-hour median intragastric pH and in terms of the number of patients achieving intragastric pH ≥4.0 for at least 12 hours per day. Nocturnal pH was measured in one of these studies, comparing esomeprazole 40 mg with pantoprazole 40 mg. During night-time the proportion of time with intragastric pH >4.0 was 85.4% with esomeprazole and 63.6% with pantoprazole (p = 0.0001). Nocturnal acid breakthrough, defined as intragastric pH <4.0 for at least one consecutive hour between 10 pm and 6 am, was observed in 26.7% of subjects receiving esomeprazole and in 73.3% of those receiving pantoprazole (p = 0.009). Data on the effect of esomeprazole on nocturnal pH in comparison with other PPIs are otherwise largely lacking.[2]

Non-erosive GERD

In one of these papers (Armstrong et al 2004), three studies were reported comparing A (n = 1282) esomeprazole 40 mg, esomeprazole 20 mg, or omeprazole 20 mg od; B (n = 693) esomeprazole 40 mg or omeprazole 20 mg od; and C (n = 670) esomeprazole 20 mg or omeprazole 20 mg od. Resolution of heartburn at 4 weeks (no heartburn symptoms during the last 7 days) was achieved in similar proportions of patients in each treatment arm in study A (esomeprazole 40 mg, 56.7%; esomeprazole 20 mg, 60.5%; omeprazole 20 mg, 58.1%), study B (esomeprazole 40 mg 70.3%; omeprazole 20 mg 67.9%), and study C (esomeprazole 20 mg 61.9%; omeprazole 20 mg, 59.6%). There were no significant differences between treatment groups within each study. Thus, not only were esomeprazole and omeprazole treatments comparable but also esomeprazole 40 mg and esomeprazole 20 mg od did not yield significantly different results after 4 weeks in patients with NERD.

Long-term (6 month) on-demand esomeprazole treatment has been reported to be superior to placebo in the therapy of patients with NERD as assessed in two double-blind, randomized clinical trials in which NERD patients were included after achieving complete resolution of heartburn after short-term esomeprazole or omeprazole treatment. In one of these, 342 patients with NERD were randomized to receive either esomeprazole 20 mg or placebo on demand for 6 months. The proportion of patients who discontinued treatment due to insufficient control of heartburn was significantly higher among placebo compared to esomeprazole recipients (51% vs 14%, p < 0.0001). In the second study, 721 patients were randomized to esomeprazole 20 mg, 40 mg, or placebo on demand for 6 months. During this period, 42% of placebo recipients discontinued treatment due to unwillingness to continue, compared with 8% and 11% of esomeprazole 20 mg and 40 mg recipients, respectively. Although a p < 0.0001 was calculated for comparisons between either esomeprazole group and placebo, no significant difference was observed between the esomeprazole treatment groups (p = 0.15). Thus the authors concluded that esomeprazole 20 mg is superior to placebo for on-demand treatment of NERD and that a higher esomeprazole dose does not confer additional clinical benefit. However, it should be pointed out that almost 60% (58%) of patients who were randomized to placebo were willing to continue treatment. These results clearly indicate that not all patients who have had resolution of symptoms after 4 weeks of PPI therapy will need continuous treatment in the future.[3]

In certain situations, it is reasonable to use higher than approved doses of PPIs, often divided in two doses. These include a diagnostic trial for noncardiac chest pain, empiric treatment trial for supraesophageal symptoms of GERD, cases of partial response to standard dose therapy, cases with breakthrough symptoms, GERD patients with severe esophageal dysmotility, and Barrett’s esophagus. A recent double-blind, randomized, cross-over study investigated the 24-hour intragastric pH profile of esomeprazole 40 mg bd vs 20 mg bd vs 40 mg od in 25 healthy volunteers. Esomeprazole 40 mg bd provided a mean time of 19.2 hours with intragastric pH >4.0 (80.1% of a 24-hour time period, 95% confidence interval (CI) 74.5%–85.7%) vs 14.2 hours with 40 mg od (59.2%, 95% CI 53.7%–64.7%) and 17.5 hours with 20 mg bd (73.0%, 95% CI 67.4%–78.5%). The percentage of time of a 24-hour period that pH remained >4.0 was significantly higher with the esomeprazole bd dosing regimens compared to the 40 mh od regimen during the supine (sleeping) portion of the monitoring period (83.7% (95% CI 74.9%–92.4%) for esomeprazole 40 mg bd vs 79.2% (95% CI 70.5%–87.9%) for esomeprazole 20 mg bd vs 57.9% (95% CI 49.0%–66.9%) for esomeprazole 40 mg od (Katz et al 2004). Esomeprazole 40 mg bd has also been shown to be superior to pantoprazole 40 mg bd and lansoprazole 30 mg bd in maintaining intragastric pH at 4.0 or lower. These data indicate that twice-daily dosing of omeprazole provides significantly greater acid suppression than once-daily dosing and may, therefore, be a reasonable consideration for patients requiring greater acid-suppression for GERD.

References

[1] HARBIN ZHENBAO PHARMACEUTICAL - CN103936715, 2016, B

[2] Armstrong D, Talley NJ, Lauritsen K, et al. The role of acid suppression in patients with endoscopy-negative reflux disease: the effect of treatment with esomeprazole or omeprazole. Aliment Pharmacol Ther. 2004;20:413–21.

[3] Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole 40 mg. compared with lansoprazole 30 mg. in the treatment of erosive esophagitis. Am J Gastroenterol. 2002;97:575–83.

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