Mohammad Niazi

Intravenous esomeprazole (40 mg and 20 mg) inhibits gastric acid secretion as effectively as oral esomeprazole: results of two randomized clinical studies

Objectives Two studies compared the effects of intravenous (i.v.) and oral esomeprazole (40 mg and 20 mg) on gastric acid suppression and pharmacokinetics after both single (day 1) and repeated (day 5) dosing. Methods Two randomized, two-way, cross–over, comparative studies of similar design were performed in healthy male and female volunteers. In both studies, subjects received esomeprazole as a 30-min i.v. infusion or orally once-daily for 5 days, separated by a wash-out period of at least 13 days. In one study, which was double-blind (double dummy), subjects received 40 mg esomeprazole. In the other open study, subjects were given 20 mg esomeprazole. Results In total, 40 and 24 subjects were randomized for treatment with 40 mg and 20 mg esomeprazole, respectively. No significant differences were found between i.v or oral administration of esomeprazole with respect to the amount of time with mean intragastric pH>4 throughout day 1 or day 5 of treatment in the 40 mg study (day 1, 10.1 h and 8.8 h versus day 5, 15.9 h and 15.3 h, respectively) and the 20 mg study (day 1, 7.3 h and 6.6 h versus day 5, 11.9 h and 12.3 h, respectively). The area under the plasma concentration–time curve values were higher following i.v. relative to oral administration on day 1 of dosing, with less pronounced differences after repeated (day 5) dosing. Both administration routes were similarly well tolerated. Conclusions Esomeprazole, 40 mg and 20 mg i.v., provides similar levels of intragastric acid control on both day 1 and day 5 of treatment compared with oral administration.

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.

Studies in Healthy Volunteers do not Show any Electrocardiographic Effects with Esomeprazole

AbstractObjectives: Esomeprazole is the first proton pump inhibitor developed as an optical isomer. The aim of this study was to assess the potential effects of this agent on the electrocardiogram (ECG) in healthy volunteers. Study Participants and Methods: A pooled analysis was performed of 82 healthy male and female volunteers who received esomeprazole 40mg once daily in phase I open-label studies. 12-lead ECG recordings were completed at an initial screening visit (baseline) and at 1.5 and 3 hours postdose following esomeprazole administration for 5 to 7 days. The ECG recordings were interpreted by independent cardiologists blinded to the participants’ drug treatment status. Participants were not allowed to have any concomitant medication. Results: At both 1.5 and 3 hours postdose, mean changes in QT and QTc intervals were small, and there was no clinically meaningful shift in the population means. Mean QTc interval showed a slight decrease overall. For all participants, absolute interlead dispersion was well within the tolerability margin of 100msec. No abnormal T or U waves, arrhythmias or other abnormalities were noted. Esomeprazole was well tolerated and there were no clinically relevant changes in tolerability variables. Conclusions: In this study of 82 healthy young individuals, esomeprazole, at a dose of 40mg, did not exhibit clinically relevant electrocardiographic effects.

Evaluation of bioequivalence between a single-capsule formulation of esomeprazole 40 mg and acetylsalicylic acid 325 mg and the monotherapies given separately in healthy volunteers.

OBJECTIVE The aim of this study was to investigate the bioequivalence of a single oral dose of esomeprazole 40 mg and acetylsalicylic acid 325 mg when formulated as a single capsule, relative to the components given as separate monotherapies. METHODS This was an open, randomized, single-center, single-dose, 2-stage group sequential design, 2-way crossover study (NCT00688428) in 49 healthy adult volunteers (29 women). In each treatment period, subjects received a single dose of esomeprazole 40 mg and ASA 325 mg formulated as a single capsule or as separate monotherapies given in combination. Treatment periods were separated by a washout period of at least 6 days. The bioequivalence of a single-capsule formulation of esomeprazole 40 mg and ASA 325 mg relative to the monotherapies given individually was assessed by the geometric mean ratios of the area under the plasma concentration-time curve (AUC) and observed maximum plasma concentration (Cmax). If the 94% confidence interval (CI) of the geometric mean ratios of AUC and Cmax were within 0.80 - 1.25, bioequivalence would be established. A 94% CI was used to compensate for the multiple analyses of the study design, and to assure that the actual overall confidence level was 90%. RESULTS The geometric mean ratios of the AUC for esomeprazole 40 mg and ASA 325 mg when administered in the single capsule formulation, relative to the monotherapies were 0.97 (94% CI, 0.90 - 1.04) and 1.04 (94% CI, 1.00 - 1.08). The corresponding mean geometric ratios for Cmax were 0.99 (94% CI, 0.90 - 1.09) and 1.02 (94% CI, 0.92 - 1.13). CONCLUSIONS Treatment with esomeprazole 40 mg and ASA 325 mg formulated as a single capsule is bioequivalent to the separate monotherapies of esomeprazole 40 mg and ASA 325 mg when given in combination as separately-administered drugs in healthy adult subjects.

Pharmacokinetic profile of lesogaberan (AZD3355) in healthy subjects: a novel GABA(B)-receptor agonist reflux inhibitor.

AbstractObjective: The aim of this study was to evaluate the pharmacokinetic profile of lesogaberan in healthy subjects after single oral and intravenous administration of 14C-labeled lesogaberan and non-14C-labeled lesogaberan. Study Design: This was an open-label, single-center, randomized, two-way crossover, phase I study. Participants: Ten healthy male subjects took part in the study. Intervention: Volunteers were randomized to receive a single dose of either orally dosed (100 mg) or intravenously infused (20 mg) non-14C-labeled lesogaberan, and then orally (100 mg) or intravenously (20 mg) administered 14C-labeled lesogaberan in a crossover design. Treatment periods were separated by a washout period of at least 7 days. Main Outcome Measures Analyses of the rate and route of excretion, dose recovery, area under the plasma concentration versus time curve (AUC), AUC to the last quantifiable concentration, maximal plasma concentration (Cmax), time to Cmax, the apparent elimination half-life, bioavailability, total clearance, renal clearance, fraction of the bioavailable dose excreted unchanged in the urine, cumulative amount of drug excreted unchanged in urine, and the apparent volume of distribution at steady state of lesogaberan. Results: Lesogaberan was rapidly and extensively absorbed from the gastrointestinal tract and Cmax was achieved within 1–2 hours of oral dosing. The terminal half-life of lesogaberan was between 11 and 13 hours. Renal clearance accounted for approximately 22% of total body clearance. Based on the recovery of administered radioactivity, approximately 84% of the dose was excreted into the urine either as the parent compound or as water-soluble metabolite(s). There were no safety concerns raised during the study. Conclusion: Orally administered lesogaberan is rapidly absorbed with high bioavailability and the majority of the dose is excreted by the kidneys either as the parent compound or as metabolites. The major elimination pathway for lesogaberan in man is metabolism.

Intravenous Esomeprazole 40mg is Effective for the Control of Intragastric Acid Levels Whether Given as a 3-Minute Injection or a 30-Minute Infusion.

AbstractBackground: An intravenous (IV) formulation of esomeprazole has been developed as an alternative to oral administration. To meet the needs of different clinical situations it would be preferable if an IV dose could be administered as either an injection or an infusion, while producing similar effects. Aim: To compare the effects of IV esomeprazole 40mg given as a 3-minute injection or a 30-minute infusion on intragastric pH during single and repeated once-daily dosing in healthy subjects. Methods: In this single-centre, double-blind, double-dummy, randomised, two-way crossover study, subjects were randomised to receive either a 3-minute IV injection or a 30-minute IV infusion of esomeprazole 40mg. Both regimens were given once daily for 10 days. After a washout period of at least 13 days, subjects were crossed over to the other treatment. Intragastric pH monitoring was performed on days 1 and 10. Blood samples were also taken throughout days 1 and 10. Results: Data were available from 41 subjects. Time with intragastric pH >4 was 3.1h/24h at baseline, increasing to almost 8h in association with IV esomeprazole injection or infusion on day 1, and to >13h on day 10. Geometric mean time with pH >4/24h ratios (injection/infusion) were 0.99 on day 1 and 1.03 on day 10. Mean esomeprazole AUC values were approximately 15% higher with the injection than the infusion, but 90% CI limits for geometric mean AUC ratios ranged from 1.07 to 1.23, indicating bioequivalence. Conclusions: IV esomeprazole 40mg provides similarly potent acid control whether administered by injection or infusion.

Evaluation of the Pharmacokinetic Interaction between Lesogaberan (AZD3355) and Esomeprazole in Healthy Subjects

AbstractBackground: Transient lower esophageal sphincter relaxations (TLESRs) have been identified as a primary cause of reflux events in patients with gastroesophageal reflux disease (GERD). GABAB receptor agonists such as lesogaberan (AZD3355) have been shown to inhibit TLESRs in healthy subjects and patients with GERD, and, therefore, offer a novel therapeutic add-on strategy to acid suppression for the management of GERD. As lesogaberan is being developed as an add-on treatment for the management of patients with GERD who have a partial response to proton pump inhibitor (PPI) therapy, it is important to rule out any clinically important pharmacokinetic drug-drug interaction between lesogaberan and PPIs. Objective: To evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa. Study Design: This was an open-label, randomized, three-way crossover study. The study was open to healthy adult male and female subjects. The study subjects received treatment with, in random order, lesogaberan (150mg twice daily [dose interval 12 hours]), esomeprazole (40 mg once daily), and a combination of both, during 7-day treatment periods. Main Outcome: The presence or absence of pharmacokinetic interactions between lesogaberan and esomeprazole was assessed by measuring the steady-state area under the plasma concentration-time curves during the dosing interval (AUCτ) and the maximum observed plasma concentration (Cmax) for lesogaberan and esomeprazole. Results: Thirty male subjects (mean age 23.2 years, 97% Caucasian) were randomized to treatment and 28 subjects completed the study (one subject was lost to follow-up, and one subject discontinued due to an adverse event). The 95% confidence intervals of the geometric mean ratios for AUCτ and Cmax of lesogaberan and esomeprazole administered alone and concomitantly were within the recognized boundaries of bioequivalence (0.8–1.25). No new safety concerns were raised during this study. The number of patients with adverse events during treatment with lesogaberan alone (n = 17) and concomitantly with esomeprazole (n = 18) were comparable but higher than with esomeprazole alone (n = 10). Paresthesia (episodic, mild, and transient), pharyngitis, and flatulence were the most frequently reported adverse events. Conclusions: There was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated. Trial registration number (clinicaltrials.gov): NCT00684190

Effect of food on the bioavailability of lesogaberan given as an oral solution or as modified-release capsules in healthy male volunteers.

The novel Type B gamma-aminobutyric acid (GABAB)-receptor agonist lesogaberan (AZD3355) has been evaluated as an add-on to proton pump inhibitor treatment for gastroesophageal reflux disease, but the effect of food on the bioavailability of this compound has not been assessed. In this openlabel crossover study, healthy males received single 100 mg doses of lesogaberan (oral solution (A) or oral modified release (MR) capsules with a dissolution rate of 50% (B) or 100% (C) over 4 h) with and without food. Blood plasma concentrations of lesogaberan were assessed over 48 h. A log-transformed geometric mean Cmax and AUC ratio within the 90% confidence interval (CI) range (0.80 - 1.25) was defined as excluding a clinically relevant food effect. Overall, 57 subjects completed the study. Only the oral lesogaberan solution had a fed/fasting Cmax ratio outside the 90% CI range (Cmax ratio: 0.76). AUC ratios were within the 90% CI limits for all three lesogaberan formulations. The only substantial change in tmax associated with food intake was observed for the oral solution (1.0 h without food, 1.8 h with food). In conclusion, a clinically relevant food effect could be excluded for the lesogaberan MR formulations, but not for the oral lesogaberan solution.

M1911 Effect of Food On the Bioavailability of AZD3355, a Novel Reflux Inhibitor, in Healthy Subjects

G A A b st ra ct s (vomiting, dehydration, apnea, and stridor). Conclusions: In infants aged 1 through 11 mo with a clinical diagnosis of GERD, the 1.2-mg/kg equivalent dose provided statistically significant increases in mean gastric pH and percentage of time with gastric pH >4, and decreases in normalized AUC of esophageal H+ activity compared to baseline. For both doses, esophageal reflux area and normalized AUC of esophageal H+ activity decreased, indicating that the increase in the gastric pH did, in fact, result in a reduction of the pH of the refluxate. Both doses were well tolerated. The results support the choice of the 1.2mg/kg dose for infants 1 through 11 months when short-term treatment with pantoprazole is being considered.