The effects of dose and timing of esomeprazole administration on 24-h, daytime and night-time acid inhibition in healthy volunteers.

BACKGROUND: Symptoms of gastro-oesophageal reflux disease (GERD) may persist despite daily treatment with a proton pump inhibitor (PPI). AIM: To compare the pharmacodynamic effect of various esomeprazole dosage and timing regimens in healthy volunteers. METHODS: The effect of different esomeprazole dosage regimens [20 mg once daily (od) before breakfast or dinner; 20 mg twice daily (b.d.); 40 mg od before breakfast, dinner or at bedtime; and 40 mg b.d.] on 24-h, daytime and night-time acid inhibition was evaluated in a randomized, seven-way crossover study in healthy volunteers. Each regimen was taken for 5 days. RESULTS: Over the 24-h period (day 5), esomeprazole 20 mg b.d. was associated with superior acid inhibition vs. all 20 mg and 40 mg od regimens (P < 0.05), but was less effective than esomeprazole 40 mg b.d. (P < 0.05). Dosing with esomeprazole 20 mg or 40 mg od before breakfast gave improved 24-h and daytime acid inhibition vs. the corresponding administration before dinner or at bedtime (all P < 0.05). Night-time acid inhibition was improved when esomeprazole 40 mg od was administered before dinner or at bedtime vs. before-breakfast dosing (P < 0.05). CONCLUSION: Varying the dose and timing of esomeprazole administration may provide acid inhibition appropriate for the symptom pattern of individual patients with GERD.

A model of healing of Los Angeles grades C and D reflux oesophagitis: is there an optimal time of acid suppression for maximal healing?

BACKGROUND: In patients with Los Angeles (LA) grade C or D oesophagitis, a positive relationship has been established between the duration of intragastric acid suppression and healing. AIM: To determine whether there is an apparent optimal time of intragastric acid suppression for maximal healing of reflux oesophagitis. METHODS: Post hoc analysis of data from a proof-of-concept, double-blind, randomized study of 134 adult patients treated with esomeprazole (10 or 40 mg od for 4 weeks) for LA grade C or D oesophagitis. A curve was fitted to pooled 24-h intragastric pH (day 5) and endoscopically assessed healing (4 weeks) data using piecewise quadratic logistic regression. RESULTS: Maximal reflux oesophagitis healing rates were achieved when intragastric pH >4 was achieved for approximately 50-70% (12-17 h) of the 24-h period. Acid suppression above this threshold did not yield further increases in healing rates. CONCLUSION: After 4 weeks' acid-suppressive therapy for LA grade C or D oesophagitis, successful healing appears to reach a threshold above which improvements are unlikely to be achieved despite an increase in number of hours with intragastric pH >4.

Suppression of gastric acid with intravenous esomeprazole and omeprazole: results of 3 studies in healthy subjects.

OBJECTIVE: To identify the optimal pharmacodynamic dosing regimen for esomeprazole administered intravenously (i.v.) and to compare acid suppression with various esomeprazole i.v. and omeprazole i.v. dosing regimens. METHODS: A total of 90 healthy Helicobacter pylori-negative subjects participated in three randomized, crossover studies of esomeprazole i.v. Comparative acid output study: an open-label study that compared single 40 mg i.v. doses (administered over 30 min) of esomeprazole and omeprazole. Dose-ranging study: an open-label study that compared acid control with five different doses of esomeprazole i.v., administered over 24 h. Comparative pH study: a double-blind study that compared esomeprazole i.v. and omeprazole at doses of 80 mg (over 30 min) + 8 mg/h (for 23.5 h). RESULTS: In the comparative acid output study, estimated mean pentagastrin-stimulated acid output was reduced from 33.9 mmol/h at baseline to 5.4 mmol/h at 4 - 5.5 h with esomeprazole vs. 9.5 mmol/h with omeprazole (p < 0.001). In the dose-ranging study, the 80 + 8 mg/h regimen provided a greater mean time with pH > 6 (12.6 h) than the lower doses (11.0 and 10.7 h for 40 + 8 mg/h and 80 + 4 mg/h, respectively) and significantly more time with pH > 4 (21.5 vs. 19.7 and 19.2 h, respectively; p < 0.05). In the comparative pH study, the mean number of h with pH > 4 was similar between esomeprazole (21.4 h) and omeprazole (21.1 h). CONCLUSIONS: Esomeprazole was superior to omeprazole in reducing stimulated acid secretion. Control of intragastric pH was similar for esomeprazole and omeprazole at a dose of 80 + 8 mg/h. An esomeprazole i.v. dosage regimen of 80 + 8 mg/h appeared to be optimal for acid suppression in healthy subjects under study.

Studies on drug interactions between esomeprazole, amoxicillin and clarithromycin in healthy subjects.

OBJECTIVE: A combination of esomeprazole, amoxicillin and clarithromycin may be used for Helicobacter pylori eradication. We explored the potential for interactions between these drugs. METHODS: In 2 randomized, 4-way crossover studies, healthy CYP2C19 extensive metabolizers (EMs) received esomeprazole 40 mg once daily (n = 20) or 20 mg twice daily (b.i.d.) (n = 20), clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d. or the combination of the 3 drugs for 7 days. In a third randomized, 2-way, crossover study, 6 healthy CYP2C 19 poor metabolizers (PMs) received esomeprazole 40 mg once daily with and without clarithromycin 500 mg b.i.d. for 1 week. RESULTS: Triple therapy with esomeprazole 40 mg increased the area under the plasma concentration-time curve during the dosing interval (AUCtau) from 13.31 micromol x h/l (11.12-15.93) for esomeprazole alone to 22.69 micromol x h/l (18.94-27.17) for triple treatment. Respective AUCtau values with esomeprazole 20 mg b.i.d. were 4.97 micromol.h/l (3.97-6.21) and 11.29 micromol x h/l (9.03-14.12). Clarithromycin and amoxicillin plasma levels were largely unchanged by combination therapy. In PMs, the esomeprazole AUC also approximately doubled when administered in combination with clarithromycin. All treatments were well tolerated. CONCLUSION: Clarithromycin decreases the metabolism rate of esomeprazole, leading to approximately doubled AUC values, both in EMs and PMs.

A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects.

OBJECTIVE: To investigate the pharmacokinetics of S-omeprazole (esomeprazole), R-omeprazole and racemic omeprazole following single and repeated oral doses of 20 mg and 40 mg of each compound in healthy male and female subjects. METHODS: In an open, randomised, three-way, cross-over study, 12 subjects received 20 mg and another 12 subjects received 40 mg S-omeprazole, R-omeprazole and racemic omeprazole as oral solutions once daily for 5 days, separated by washout periods of at least 10 days. Blood samples were taken for analysis pre-dose and at selected time points during a 12-h period following drug administration on study day 1 and day 5. Pharmacokinetic parameters of S-omeprazole, R-omeprazole, racemic omeprazole and the two main metabolites (5-hydroxy and sulphone) were calculated using non-compartmental analysis. RESULTS: Following the 20-mg dose of each compound, values of the total area under the plasma concentration-time curve (AUC) were 1.52, 0.62 and 1.04 micromol h/l for S-omeprazole, R-omeprazole and racemic omeprazole, respectively, on day 1. Respectively, AUC values on day 5 were 2.84, 0.68 and 1.63 micromol h/l. Corresponding values after the 40-mg doses were 3.88, 1.39 and 2.44 micromol h/l on day 1 and 9.32, 1.80 and 5.79 micromol h/l on day 5. CONCLUSION: Treatment with S-omeprazole (esomeprazole; 20 mg and 40 mg) resulted in higher AUC values than with either R-omeprazole or racemic omeprazole after both single and repeated doses due to a lower metabolic rate of S-omeprazole than R-omeprazole and, consequently, racemic omeprazole. S-Omeprazole, R-omeprazole and the racemate were well tolerated.

Esomeprazole 40 mg i.v. provides faster and more effective intragastric acid control than pantoprazole 40 mg i.v.: results of a randomized study.

BACKGROUND: Oral esomeprazole 40 mg provides greater acid control than oral pantoprazole 40 mg. AIM: To compare the effects on intragastric acid control of esomeprazole 40 mg administered intravenously with pantoprazole 40 mg intravenously. METHODS: Healthy Helicobacter pylori-negative male and female subjects were enrolled into this single-centre, open, randomized, two-way crossover study. Esomeprazole 40 mg intravenously and pantoprazole 40 mg intravenously were administered as 15-min infusions once daily at 09:00 hours for 5 days. Continuous 24-h intragastric pH monitoring was carried out at baseline and on days 1 and 5. RESULTS: pH-data were available for all 25 subjects who completed the study. Esomeprazole 40 mg intravenously resulted in 8.3 and 13.9 h with an intragastric pH > 4 on days 1 and 5 compared with 5.3 and 9.0 h, respectively for pantoprazole 40 mg intravenously (day 1: P < 0.001, day 5: P < 0.0001). During the first 4 h of dosing on day 1 corresponding values were 1.7 and 0.6 h respectively (P < 0.0001). A mean median pH above 4 on day 5 was only attained with esomeprazole 40 mg intravenously. CONCLUSIONS: Once-daily dosing with esomeprazole 40 mg intravenously provides faster and more pronounced intragastric acid control than pantoprazole 40 mg intravenously.

Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole.

BACKGROUND: Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor developed as a single isomer for the treatment of acid-related diseases. AIM: To examine the pharmacokinetics and pharmacodynamics of esomeprazole. METHODS: In a crossover study, 12 healthy males received 5, 10 or 20 mg of esomeprazole, or 20 mg of omeprazole, once daily over 5 days. The pharmacokinetics and effects on pentagastrin-stimulated peak acid output of esomeprazole and omeprazole were studied on days 1 and 5. RESULTS: The area under the curve (AUC) of both esomeprazole and omeprazole increased from day 1 to day 5. The correlation between acid inhibition and AUC for esomeprazole could be well described with a sigmoid Emax model. The mean inhibition values of the pentagastrin-stimulated peak acid output on day 1 for 5, 10 and 20 mg of esomeprazole were 15%, 29% and 46%, respectively; the corresponding day 5 values were 28%, 62% and 90%. The mean inhibition values of the pentagastrin-stimulated peak acid output for omeprazole were 35% (day 1) to 79% (day 5). CONCLUSIONS: The pharmacokinetics of esomeprazole are time and dose dependent. There was a good correlation between AUC and effect for esomeprazole. These data suggest an increased acid inhibitory effect of esomeprazole compared to omeprazole.

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) 1 A2, 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.

Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole.

This 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 metabo- lites 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.

Pharmacokinetic study of esomeprazole in the elderly.

OBJECTIVE: Esomeprazole 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-oesophageal reflux disease (GORD). DESIGN: Nonblinded single-centre pharmacokinetic study with historical control group. PATIENTS AND PARTICIPANTS: 14 healthy elderly volunteers [mean age 74 (range 71 to 80) years]. METHODS: Participants received treatment with esomeprazole 40 mg once daily for 5 days, with 24-hour blood sampling on days 1 and 5. The total area under the plasma concentration-time curve (AUCinfinity), maximum plasma drug concentration (Cmax), terminal elimination half-life (t(1/2z)) and time to Cmax (tmax) were determined for the parent drug and its hydroxy and sulphone metabolites. AUCinfinity 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. RESULTS: A total of 13 volunteers completed the study. On day 5, the mean plasma AUCinfinity of esomeprazole was 16.0 micromol x h/L, Cmax was 5.6 micromol/L, tmax was 1.5 hours and t(1/2z) was 1.7 hours. The AUCinfinity and Cmax values for the parent drug were 2- and 1.5-fold higher on day 5 compared with day 1. AUCinfinity and Cmax values for the sulphone metabolite increased to a slightly greater extent, and values for the hydroxy metabolite were unchanged. Ratios of the AUCinfinity 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. CONCLUSIONS: The AUCinfinity and Cmax values in the elderly were not significantly different from those obtained in a group of middle-aged patients. The difference for AUCinfinity 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.

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

BACKGROUND: Esomeprazole (Nexium) is a new proton pump inhibitor for the treatment of acid-related diseases. METHODS: In this double-blind crossover study, 38 patients with gastro-oesophageal reflux disease (GERD) symptoms were randomized to esomeprazole 40 and 20 mg and omeprazole 20 mg once daily for 5 days. On day 5 of each dosing period, 24-h intragastric pH and pharmacokinetic variables were measured. RESULTS: Thirty-six patients aged 29-58 (mean 45) years completed the study. Esomeprazole 40 and 20 mg maintained intragastric pH > 4 for (mean) 16.8 and 12.7 h, respectively, vs. 10.5 h for omeprazole 20 mg (P < 0.001 and P < 0. 01). Twenty-four-hour median intragastric pH was significantly higher with esomeprazole 40 mg (4.9) and 20 mg (4.1) than with omeprazole 20 mg (3.6) (P < 0.001 and P < 0.01). Area under the plasma concentration-time curve (AUC) was 80% higher for esomeprazole 20 mg vs. omeprazole, while that for esomeprazole 40 mg was more than five times higher (each P < 0.0001). Interpatient variability in intragastric pH and AUC was less with esomeprazole than with omeprazole. Esomeprazole was well tolerated and there were no safety concerns. CONCLUSIONS: Esomeprazole provides more effective acid control than omeprazole, with reduced interpatient variability, thereby offering the potential for improved efficacy in acid-related diseases.

Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects.

OBJECTIVE: To study the pharmacokinetics of esomeprazole, one of the optical isomers of omeprazole, after 20 mg or 40 mg single and repeated oral and intravenous administration to healthy subjects. The main metabolites of esomeprazole were also assessed after the 40-mg oral dose. METHODS: In two separate studies, 16 healthy male subjects and 16 healthy male and female subjects received intravenous doses of 20 mg and 40 mg esomeprazole, respectively, on the first investigation day. After a washout period of 5-14 days, the same doses (20 mg as a solution and 40 mg as a capsule) were given orally for 5 days and then again intravenously on day 6. Blood samples for determination of esomeprazole and its metabolites were collected 12 h or 24 h post-dose and were analysed using normal-phase liquid chromatography with ultraviolet (UV) detection. Pharmacokinetic parameters of esomeprazole and its metabolites were estimated using non-compartmental analysis. Geometric means and ratios of the geometric means together with 95% confidence intervals (CI) of the pharmacokinetic parameters were calculated using analysis of variance (ANOVA). RESULTS: Plasma clearance (CL) of esomeprazole decreased from 22 l/h to 16 l/h and from 17 l/h to 9 l/h following repeated dosing of 20 mg and 40 mg, respectively. Total area under the plasma concentration-time curve (AUC) increased (from 1.34 micromol x h/l to 2.55 micromol x h/l) with absolute bioavailability (F) being 50% on day 1 and 68% on day 5 after the 20-mg oral dose. AUC increased (from 4.32 micromol x h/l to 11.21 micromol x h/l) with F being 64% on day 1 and 89% on day 5 after the 40-mg oral dose. The plasma levels for esomeprazole sulphone were substantially higher on day 5 than on day 1, while those for 5-hydroxy esomeprazole were marginally higher on day 5 than on day 1 following repeated oral dosing of 40 mg esomeprazole. No side effects attributable to esomeprazole were noticed. CONCLUSION: The increased AUC of esomeprazole with repeated dosing is probably due to a combination of a decreased first-pass elimination and a decreased systemic clearance.

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.

The effect of mosapride, a novel prokinetic, on acid reflux variables in patients with gastro-oesophageal reflux disease.

BACKGROUND: Mosapride is a novel prokinetic agent facilitating acetylcholine release from the enteric cholinergic neurones through a selective 5-HT4 receptor agonistic action. It is also active through its main metabolite M1, which is a 5-HT3 antagonist. The importance of motor dysfunction in the pathogenesis of gastro-oesophageal reflux disease (GERD) makes it interesting to examine the effect of mosapride on oesophageal acid exposure. METHODS: The effect of mosapride on oesophageal 24-h acid reflux variables was studied in 21 patients with GERD symptoms and a pre-entry total acid exposure time (pH < 4) of more than 5%. Ambulatory pH monitoring was performed after treatment with 40 mg mosapride citrate or placebo q.d.s. for 2 days in random order, using a double-blind crossover technique, with a washout period of at least 5 days. RESULTS: Mosapride was significantly more effective than placebo in decreasing the total number of reflux episodes, the total number of reflux episodes lasting more than 5 min and the total time, as well as the amount of day time, of intra-oesophageal pH below 4. Consequently, mosapride also significantly improved total acid clearance time. CONCLUSION: Mosapride 40 mg q.d.s. is effective in decreasing acid reflux in the oesophagus in patients with GERD and therefore has the potential to be effective in the treatment of this disease.

Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole.

AIMS: To study the pharmacokinetics of three proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole, as well as any potential influence on CYP1A2 activity (measured by means of rate of caffeine metabolism) of these compounds at single dose and repeated dose administration. METHODS: Fourteen healthy males, classified as 12 extensive metabolizers (EMs) and two poor metabolizers (PMs) according to the urinary S/R mephenytoin ratio, completed this open, randomized, three-way cross-over study. In each of the three 7-day treatment periods either omeprazole (20 mg), lansoprazole (30 mg) or pantoprazole (40 mg) in therapeutically recommended doses was administered once daily, and the pharmacokinetics of the proton pump inhibitors as well as the rate of caffeine metabolism was measured on days 1 and 7. RESULTS: In the EMs there was an increase in AUC from day 1 to day 7 for omeprazole. In the PMs the AUC of both omeprazole and lansoprazole was unchanged during repeated dosing, while for pantoprazole there was a tendency to a slight decrease. The AUC at steady state was for all three proton pump inhibitors 5 fold higher in PMs compared with EMs, indicating that the same proportion of the dose, irrespective of compound, is metabolized by CYP2C19. No induction of CYP1A2 was evident for any of the compounds in either EMs or PMs. CONCLUSIONS: The approximately 5 fold difference in AUC between EMs and PMs indicates that approximately 80% of the dose for all three proton pump inhibitors is metabolized by the polymorphically expressed CYP2C19. None of the three proton pump inhibitors, administered in therapeutically recommended doses, is an inducer of CYP1A2--neither in PMs nor in EMs.

Pharmacokinetics and pharmacodynamics during treatment with the omeprazole 20 mg enteric-coated tablet and 20 mg capsule in asymptomatic duodenal ulcer patients.

This study compared the 24 h intragastric pH profile and bioavailability at repeated dosing conditions of the omeprazole 20 mg enteric-coated tablet versus the 20 mg capsule. Forty duodenal ulcer patients in asymptomatic remission completed this randomized open two-way crossover study. Omeprazole 20 mg tablets or capsules were administered for seven days in each period. A 24 h pH recording was performed before the start of treatment and on day 7 of each treatment period. Plasma concentrations of omeprazole were determined 24 h after the dose. The treatment periods were separated by two to four weeks. The difference in percentage of time with pH of at least 3 was less than 16% in favour of the tablet (not significant). The estimated mean area under the plasma concentration-time curve as well as the maximum plasma concentration (Cmax) for omeprazole were 18% and 41% higher, respectively, for the tablet versus the capsule, with the latter percentage being statistically significant. The time to reach Cmax (tmax) with the tablet was, on average, about 0.5 h longer than to reach the tmax of the capsule. This study indicates that the enteric-coated tablet formulation of omeprazole is biodynamically equivalent to the capsule regarding their effects on intragastric pH during repeated dosing.

Effect of once daily intravenous and oral omeprazole on 24-hour intragastric acidity in healthy subjects.

The effect of repeated once daily administration of 20 mg omeprazole orally and 10 mg and 40 mg intravenously on 24-h intragastric acidity was studied in nine healthy subjects. On day 1, 20 mg orally and 10 mg intravenously reduced integrated intragastric acidity by 18% and 15%, respectively (NS). On day 5 the reduction had increased to 60% and 53%, respectively (p < 0.05). The first dose of 40 mg intravenously produced a reduction of 71% (p < 0.05) with no further increase during continued administration. An increase in plasma omeprazole concentrations by 56% (p < 0.05) was seen during repeated dosing with 40 mg intravenously, while no significant change occurred with the two other doses. Thus once daily administration of 10 mg omeprazole intravenously produced an effect on 24-h intragastric acidity comparable to that of once daily administration of 20 mg omeprazole orally. However, for both these dosage regimens it took a few days before their maximal effect was obtained. Parenteral administration of 40 mg omeprazole produced, already on the first day of treatment, an effect similar to that seen after 5 days of oral administration of 20 mg omeprazole or intravenous administration of 10 mg and can therefore overcome this initial delay in drug action. The reduction of 24-h intragastric acidity seen in the present study appeared to be lower than that seen in a similar study in duodenal ulcer patients, a finding not explained by differences in age or pharmacokinetics.

Comparison of once-daily intravenous and oral omeprazole on pentagastrin-stimulated acid secretion in duodenal ulcer patients.

The effect of 5 days of once-daily dosing with 20 mg p.o. and 40 mg i.v. omeprazole on pentagastrin-stimulated acid secretion was studied in 8 patients with duodenal ulcer. In addition they also received a 10-mg i.v. dose on day 6 during the oral treatment period. The antisecretory effect was measured 6-7 h after dose at a time point when maximal inhibition during the dosing interval is anticipated. The median percent inhibition of peak acid output (PAO) markedly increased from 43% on day 1 to 100% on day 5 during treatment with 20 mg p.o. The first 40-mg i.v. dose produced a median inhibition of 98% of PAO already on day 1. After 5 days of dosing, the inhibition had increased to 100%. On the other hand, a 10-mg i.v. dose could essentially maintain the degree of PAO reduction reached after 5 days of oral treatment. Plasma omeprazole concentrations increased during repeated dosing both with 20 mg p.o. and 40 mg i.v.

Effect of single and repeated intravenous doses of omeprazole on pentagastrin stimulated gastric acid secretion and pharmacokinetics in man.

Single intravenous doses of 10, 20, 40, and 80 mg and repeated once daily intravenous doses of 10 and 20 mg omeprazole induced a powerful and long lasting inhibition of pentagastrin stimulated gastric acid secretion (PAO) in healthy male volunteers. Single intravenous doses of 10, 20, 40, and 80 mg omeprazole inhibited PAO by 30% (p less than 0.01), 45% (p less than 0.01), 61% (p less than 0.01), and 80% (p less than 0.01), respectively when measured 1.5 h after dose, and by 20% (NS), 27% (NS), 36% (p less than 0.01) and 59% (p less than 0.01), respectively when measured 24 h after dose. Six days after repeated once daily intravenous doses of 10 and 20 mg omeprazole, PAO was inhibited by 63% (p less than 0.01) and 82% (p less than 0.01), respectively when measured 1.5 h after dose, and by 32% (p less than 0.01) and 43% (p less than 0.01), respectively when measured 24 h after dose. The inhibition of PAO by 10 mg administered intravenously as a single bolus injection was comparable with the inhibition by 20 mg as a single oral dose. Repeated once daily administration of 10 mg intravenously and 20 mg orally also resulted in comparable reductions in PAO. The reduction in PAO after repeated once daily oral administration of 20 mg was comparable with the effect of a single intravenous dose of 40 mg. Terminal half lives were short, but significantly (p less than 0.05) prolonged after a single intravenous injection of 80 mg. Repeated once daily intravenous administration of 10 and 20 mg did not result in prolongation of terminal half lives. It is concluded that intravenous administration of omeprazole causes a potent and long acting inhibition of pentagastrin stimulated gastric acid secretion in man. Its potency is augmented after repeated once daily administration.

Lack of effect of antacids on plasma concentrations of omeprazole given as enteric-coated granules.

Twelve male volunteers were studied after a single oral dose of 20 mg omeprazole given as enteric-coated granules with and without concomitant administration of 10 ml of a potent liquid antacid (buffering capacity 56.6 mmol 10 ml-1) under fasting conditions. No statistically significant differences were detected in median Cmax (0.41 approximately equal to 0.53 mumol l-1), the geometric mean AUC (0.80 approximately equal to 0.81 mumol l-1 h) or median tmax (1.25 h), with and without antacid.