Göran Hasselgren

Esomeprazole provides improved acid control vs. omeprazole in patients with symptoms of gastro‐oesophageal reflux disease

Esomeprazole (Nexium) is a new proton pump inhibitor for the treatment of acid‐related diseases.

Pharmacokinetic Studies with Esomeprazole, the (S)-Isomer of Omeprazole

AbstractThis article reviews the pharmacokinetics of esomeprazole, the (S)-isomer of the proton pump inhibitor (PPI) omeprazole. Esomeprazole is the first single isomer PPI developed for the treatment of patients with acid-related diseases. In vitro experiments in human liver microsomes demonstrated that the formation of the hydroxy and 5-O-desmethyl metabolites of esomeprazole is via cytochrome P450 (CYP) 2C19, whereas that of the sulphone metabolite is via CYP3A4. The formation rate of the hydroxy metabolite from esomeprazole is lower than for (R)-omeprazole, but that of the 2 other metabolites is higher, demonstrating stereoselective metabolism. The sum of the intrinsic clearances of all 3 metabolites for esomeprazole was one-third of that for (R)-omeprazole, suggesting lower clearance of esomeprazole in vivo.In vivo investigations demonstrated that esomeprazole is chirally stable after administration. Esomeprazole is 97% bound to plasma proteins. In normal (extensive) metabolisers with regard to CYP2C19, esomeprazole is metabolised more slowly than omeprazole, resulting in a higher area under the concentration-time curve (AUC) after administration of the same dose. This is more pronounced after repeated administration rather than after a single dose. In poor metabolisers, the AUC is lower for esomeprazole than for omeprazole, contributing to less overall interindividual variability for esomeprazole than for omeprazole.In general, esomeprazole and omeprazole are subject to the same metabolic transformations. Almost complete recoveries were reported and the ratio between urinary and faecal excretion is about 4: 1 for both compounds. The dose-dependent increase in AUC of esomeprazole with repeated administration results from a combination of decreased first-pass elimination and decreased systemic clearance. Patients with gastro-oesophageal reflux disease exhibit a pharmacokinetic pattern similar to that in healthy individuals, whereas elderly individuals exhibited a slightly lower metabolism rate.Patients with a severe deficit in their liver function had a lower rate of metabolism, as would be expected, whereas those with mild to moderate liver disease did not exhibit any alteration in the pharmacokinetics. The pharmacokinetics of esomeprazole in individuals with impaired renal function is unlikely to differ from that in healthy individuals. A slight sex difference in the pharmacokinetics of esomeprazole was demonstrated in that the AUC and peak plasma drug concentration were slightly, but not statistically significantly, higher in females than in males.

Drug Interaction Studies with Esomeprazole, the (S)-Isomer of Omeprazole

Esomeprazole, the (S)-isomer of omeprazole, is the first proton pump inhibitor (PPI) developed as a single isomer for the treatment of patients with acid related diseases. Because of the extensive use of PPIs, the documentation of the potential for drug interactions with esomeprazole is of great importance.Altered absorption or metabolism are 2 of the major mechanisms for drug-drug interactions. Since intragastric pH will increase with esomeprazole treatment, it can be hypothesised that the absorption of drugs with pH-sensitive absorption (e.g. digoxin and ketoconazole) may be affected.Esomeprazole does not seem to have any potential to interact with drugs that are metabolised by cytochrome P450 (CYP) 1A2, 2A6, 2C9, 2D6 or 2E1. In drug interaction studies with diazepam, phenytoin and (R)-warfarin, it was shown that esomeprazole has the potential to interact with CYP2C19. The slightly altered metabolism of cisapride was also suggested to be the result of inhibition of a minor metabolic pathway for cisapride mediated by CYP2C19. Esomeprazole did not interact with the CYP3A4 substrates clarithromycin (2 studies) or quinidine. Since the slightly increased area under the concentration-time curve (AUC) of cisapride could be explained as an inhibition of CYP2C19, the data on these 3 CYP3A4 substrates indicate that esomeprazole does not have the potential to inhibit this enzyme.The minor effects reported for diazepam, phenytoin, (R)-warfarin, and cisapride are unlikely to be of clinical relevance. Clarithromycin interacts with the metabolism of esomeprazole resulting in a doubling of the AUC of esomeprazole. The increased plasma concentrations of esomeprazole are unlikely to have any safety implications.It can be concluded that the potential for drug-drug interactions with esomeprazole is low, and similar to that reported for omeprazole.

Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reflux disease.

Maintenance of intragastric pH > 4 is vital for effective management of gastroesophageal reflux disease (GERD). Esomeprazole 40 mg, the first proton pump inhibitor developed as an optical isomer, demonstrates improved acid inhibition over omeprazole 20 mg. Our aim was to compare esomeprazole 40 mg with omeprazole 40 mg, once-daily, on intragastric acidity in patients with symptoms of GERD. In this open-label, crossover study, 130 patients with symptoms of GERD received esomeprazole 40 mg or omeprazole 40 mg once-daily for five days. The 24-hr intragastric pH was monitored on days 1 and 5 of each treatment period. The mean percentage of the 24-hr period with intragastric pH > 4 was significantly greater (P < 0.001) with esomeprazole 40 mg than with omeprazole 40 mg on days 1 (48.6% vs 40.6%) and 5 (68.4% vs 62.0%). Interpatient variability was significantly less with esomeprazole than omeprazole. Esomeprazole was well tolerated. In conclusion, esomeprazole 40 mg provides more effective acid control than twice the standard dose of omeprazole.

One week of treatment with esomeprazole-based triple therapy eradicates Helicobacter pylori and heals patients with duodenal ulcer disease.

Background Proton pump inhibitor (PPI) monotherapy is commonly continued for 3 weeks after Helicobacter pylori eradication with PPI-based triple therapy regimens to ensure duodenal ulcer (DU) healing. This randomized, double-blind, multicentre study evaluated whether only 1 week of triple therapy with the new PPI esomeprazole was sufficient to ensure high rates of ulcer healing and H. pylori eradication. Methods A total of 446 H. pylori-positive patients with active DU received twice daily treatment with esomeprazole 20 mg (n = 222) or omeprazole 20 mg (n = 224) in combination with amoxicillin 1 g and clarithromycin 500 mg for 1 week (EAC and OAC, respectively). Patients in the OAC group then received 3 weeks’ monotherapy with omeprazole 20 mg once daily; those treated with EAC received placebo. Ulcer healing was assessed by endoscopy on completion of therapy and H. pylori status was assessed by 13C-urea breath testing and histology 4–6 weeks later. Results Ulcer healing rates (95% CI) for intention-to-treat and per-protocol populations were: EAC + placebo 91% (87–95%) and 94% (90–97%); OAC + omeprazole 92% (88–95%) and 96% (92–98%). Corresponding H. pylori eradication rates were: EAC + placebo 86% (81–90%) and 89% (84–93%); OAC + omeprazole 88% (83–92%) and 90% (85–93%). Both eradication regimens were well tolerated, and patient compliance was high. Conclusions A 1-week regimen of esomeprazole-based triple therapy is sufficient for DU healing and H. pylori eradication in patients with DU disease.

One-week triple therapy with esomeprazole provides effective eradication of Helicobacter pylori in duodenal ulcer disease

Esomeprazole is the first proton pump inhibitor to be developed as an optical isomer for the treatment of acid‐related diseases.

Optimization of acid suppression for patients with peptic ulcer bleeding : an intragastric pH-metry study with omeprazole

Objective To study whether an intravenous infusion dose of omeprazole (80 mg + 8 mg/h) during 24 h can be subsequently reduced with maintained effect. Second, to study the effect of oral omeprazole 20 mg given once or twice daily up to day 10, after cessation of a 3-day intravenous infusion (80 mg + 8 mg/h). Design Prospective, randomized, partly blinded study. Methods Twelve Helicobacter pylori(+) patients and 12 H. pylori(-) subjects were included. In part I the patients received omeprazole, 80 mg + 8 mg/h, during 24 h followed by 8, 4 or 2 mg/h. In part II the subjects received 80 mg + 8 mg/h during 3 days followed by 20 mg omeprazole orally, once or twice daily until day 10. Intragastric pH was measured. Results All H. pylori(+) patients showed a rapid increase of intragastric pH with a mean intragastric pH of 6.7 during the second half of the first day. After the subsequent dose reduction, the mean pH decreased to 6.1 −6.2. Patients continuing on 8 mg/h showed the best results. Likewise, all H. pylori(-) subjects showed a rapid and sustained reduction of intragastric acidity during the infusion. Subsequent dose reduction to 20 mg once daily led to a stable fraction of time with pH > 3 of 72%. Conclusions Omeprazole given as a continuous infusion of 80 mg + 8 mg/h for 72 h followed by omeprazole 20 mg once daily raised the intragastric pH to and above levels alleged to allow haemostasis in patients with peptic ulcer bleeding and subsequent healing of the ulcer.

Pharmacokinetic Study of Esomeprazole in the Elderly

ObjectiveEsomeprazole is the first proton pump inhibitor to be developed as an optical isomer for the treatment of patients with acid-related diseases. The aim of this study was to examine the pharmacokinetics and tolerability of esomeprazole in the elderly, relative to middle-aged patients with gastro-oesopha-geal reflux disease (GORD).DesignNonblinded single-centre pharmacokinetic study with historical control group.Patients and Participants14 healthy elderly volunteers [mean age 74 (range 71 to 80) years].MethodsParticipants received treatment with esomeprazole 40mg once daily for 5 days, with 24-hour blood sampling on days 1 and 5. The total area under the plasma concentration-time curve (AUC∞), maximum plasma drug concentration (Cmax), terminal elimination half-life (t1/2z) and time to Cmax (tmax) were determined for the parent drug and its hydroxy and sulphone metabolites. AUC∞ and Cmax data were compared with those in an historical group of 36 middle-aged patients [mean age 45 (range 29 to 58) years] with GORD, treated with an identical dosage of esomeprazole for 5 days.ResultsA total of 13 volunteers completed the study. On day 5, the mean plasma AUC∞ of esomeprazole was 16.0 µmol · h/L, Cmaxwas 5.6 µmol/L, tmax was 1.5 hours and t1/2z was 1.7 hours. The AUC∞ and Cmax values for the parent drug were 2- and 1.5-fold higher on day 5 compared with day 1. AUC∞ and Cmax values for the sulphone metabolite increased to a slightly greater extent, and values for the hydroxy metabolite were unchanged. Ratios of the AUC∞ and Cmax values between elderly volunteers and patients with GORD were 1.25 [95% confidence interval (CI) 0.94, 1.67] and 1.18 (0.91, 1.52), respectively. Esomeprazole was well tolerated and there were no safety concerns.ConclusionsThe AUC∞ and Cmax values in the elderly were not significantly different from those obtained in a group of middle-aged patients. The difference for AUC∞ was 25% (95% CI −6% to +67%). Esomeprazole has a wide therapeutic window and our results do not indicate that dosage adjustment should be necessary in the elderly.

Occurrence of Nighttime Gastroesophageal Reflux in Disturbed and Normal Sleepers

BACKGROUND & AIMS It is not uncommon in a sleep laboratory to encounter individuals who have complaints of disturbed sleep, but who do not meet the criteria for a sleep disorder when evaluated by polysomnography. Because gastroesophageal reflux is known to occur in many individuals without their awareness, it is possible that some of these individuals might be suffering from reflux that is disturbing their sleep. METHODS Eighty-one individuals with complaints of disturbed or unrefreshing sleep, but no complaints of heartburn, were recruited. A comparison group of 39 individuals with neither sleep nor heartburn complaints also was studied. Both groups were studied on 2 separate occasions by simultaneous polysomnography and pH monitoring to detect the presence of nighttime gastroesophageal reflux and to determine sleep outcomes. RESULTS In the disturbed-sleep group 27% of subjects had at least one reflux event compared with 33% in the normals. In the subjects who experienced reflux, the disturbed-sleep group had a significantly greater percentage of acid exposure time compared with the normals (9.5% vs 1.6%; P < .05). Participants in the disturbed-sleep group also had a longer sleep-onset latency (P < .05) and less total sleep time (P < .05) compared with the normal sleepers. CONCLUSIONS Among individuals with complaints of disturbed sleep, there was a subset of individuals who had significant gastroesophageal reflux. We speculate that sleep-related gastroesophageal reflux may play a role in producing disturbed sleep in individuals without heartburn and otherwise unexplained sleep disturbance.

Pharmacokinetic study of esomeprazole in patients with hepatic impairment

Objective To evaluate the pharmacokinetics and safety of esomeprazole (Nexium), the S-isomer of omeprazole, after repeated oral dosing in patients with hepatic impairment. Design Single-centre, open-label one-way study. Methods Twelve patients (aged 40–60 years) with mild to severe hepatic impairment received once-daily oral esomeprazole 40 mg for 5 days. Serial blood samples were drawn up to 24 h post-dose on day 5 to determine plasma levels of esomeprazole and its metabolites. Pharmacokinetic parameters were compared with an historical control group of 36 gastro-oesophageal reflux disease (GORD) patients (aged 29–58 years) with normal hepatic function. Results Esomeprazole was absorbed rapidly (mean maximum plasma concentration (Cmax) 6.1 μmol/l, mean time to Cmax (tmax) 1.9 h) and eliminated rapidly (mean plasma elimination half-life (t1/2) 2.1 h). Elimination of its pharmacologically inactive sulphone and hydroxy metabolites was more gradual. Patients with mild hepatic impairment had area under the plasma concentration–time curve during the dosage interval (AUCτ) and t1/2 values largely within the range of the control group. In patients with moderate hepatic impairment, t1/2 values were similar and AUCτ was slightly higher than in controls, whereas both parameters were increased in patients with severe hepatic impairment. The mean ratios of esomeprazole AUCτ, Cmax and t1/2 values in patients with and without hepatic impairment were 1.8, 1.3 and 1.3, respectively. Conclusions The steady-state pharmacokinetics of esomeprazole were not altered substantially by mild or moderate hepatic impairment; however, plasma levels of esomeprazole were elevated in severe cases. Thus, dose adjustment appears unwarranted in mild or moderate hepatic impairment, but may be required in some severely impaired patients. Esomeprazole was tolerated well across the spectrum of hepatic impairment.