Synchronized determination of sacubitril and valsartan with some co-administered drugs in human plasma via UPLC-MS/MS method using solid-phase extraction.

An accurate and sensitive UPLC-MS/MS method was developed and validated for the simultaneous estimation of the newly developed combination of sacubitril and valsartan and the co-administered drugs nebivolol, chlorthalidone and esomeprazole in human plasma. Solid-phase extraction was conducted for the purification and extraction of the drugs from human plasma. Chromatographic separation was carried out on an Agilent SB-C18 (1.8 µm, 2.1 × 50 mm) column using losartan as internal standard. Isocratic elution was applied using acetonitrile-0.1% formic acid in water (85: 15, v/v) as mobile phase. Detection was carried out using a triple-quadrupole tandem mass spectrometer using multiple reaction monitoring, at positive mode at m/z 412.23 → 266.19 for sacubitril, m/z 436.29 → 235.19 for valsartan, m/z 405.8 → 150.98 for nebivolol, m/z 346.09 → 198 for esomeprazole and a selected combination of two fragments m/z 423.19 → 207.14 and 423.19 → 192.2 for losartan (internal standard), and in negative ionization mode at m/z 337.02 → 190.12 for chlorthalidone. The method was linear over the concentration ranges 30-2,000 ng/ml for sacubitril, 70-2,000 ng/ml for valsartan, esomeprazole and chlorthalidone and 70-5,000 pg/ml for nebivolol. The developed method is sensitive and selective and could be applied for dose adjustment, bioavailability and drug-drug interaction studies.

Esomeprazole During Pregnancy and Lactation: Esomeprazole Levels in Maternal Serum, Cord Blood, Breast Milk, and the Infant's Serum.

Background: Esomeprazole is the S-isomer of omeprazole and is used to treat stomach acid-related diseases. Most data regarding the safety of esomeprazole during pregnancy are derived from studies on omeprazole, and the data characterizing esomeprazole transfer across the placenta and excretion into breast milk are limited. In this report, we discuss the safety of esomeprazole with reference to drug concentrations in maternal and neonatal blood and breast milk. Materials and Methods: After the patient provided informed consent, esomeprazole concentrations in maternal serum, breast milk, cord blood, and infant's serum were measured after 10 mg of maternal oral esomeprazole administration. Case Report: A 34-year-old female diagnosed with rheumatoid arthritis received esomeprazole before and during pregnancy and lactation. The esomeprazole concentration in cord blood was 40% of the level in maternal serum. At 12 hours after delivery (23.2 hours after dose), omeprazole was not detected in the infant's serum. In breast milk, esomeprazole concentrations at 0.7, 4.0, and 8.2 hours after the last dose were 10.5, 19.6, and 3.0 ng/mL, respectively, and esomeprazole was not detected at 10 hours after maternal administration. The calculated daily infant dose of esomeprazole through breast milk was 0.003 mg/[kg·day]. The infant demonstrated normal developmental progress and no detectable drug-related adverse effects. Discussion and Conclusions: Exposure to esomeprazole through placenta and breast milk was not clinically relevant in the infant. Further studies are needed to evaluate any harmful effects after exposure to esomeprazole in utero or during breastfeeding after esomeprazole treatment.

Esomeprazole vs pantoprazole effects on cyclosporine levels in kidney transplantation: A randomized clinical trial.

Renal allograft survival requires multiple immunosuppressive drugs. This strategy may lead to gastric complications that necessitate gastro-protective medications, notably, proton pump inhibitors (PPI). This study aimed to compare the influence of pantoprazole and esomeprazole on serum cyclosporine trough levels (C0 ) in renal transplant recipients (RTR). A prospective, parallel, open-label trial was conducted on 47 adult RTR receiving cyclosporine doses adjusted to attain trough concentrations of 100 to 150 µg/L, mycophenolate mofetil (MMF) 750 mg q12 hour and prednisolone at 5 mg daily at Nasser Institute, Cairo, Egypt from January to September 2016. Patients were randomized into the esomeprazole group (25) or pantoprazole group (22) receiving the same dose (40 mg once daily). The study outcomes included clinical signs of rejection and renal function decline, assessed by elevations in serum creatinine, caused by cyclosporine level variations in either of the two study groups. Renal function, C0 and CBC measurements were measured at baseline and monthly for 6 months. The mean C0 values were higher in the pantoprazole group than in the esomeprazole group in the sixth month only (P = .007). Serum creatinine level was lower in the sixth month than at baseline in the esomeprazole group (P = .004). There were no signs of rejection biochemical or clinical in any of the study groups. In conclusion, PPIs should be used with caution and doses should be titrated to reach the C0 targets in RTR, which is of more importance in pantoprazole than esomeprazole to avoid C0 level elevation or decline affecting the allograft function.

The safety, pharmacodynamics, and pharmacokinetics of immediate-release formulation containing esomeprazole 20 mg/sodium bicarbonate 800 mg in healthy adult male.

BACKGROUND: Esomeprazole is the most effective treatment for acid-related disorders and is widely used with enteric coating due to rapid degradation in the acidic environment. However, the enteric-coated formulation delays absorption and onset of action. To overcome this limitation, an immediate-release formulation containing esomeprazole 20 mg and sodium bicarbonate 800 mg (IR-ESO) was developed. PURPOSE: To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics of IR-ESO compared to those of esomeprazole 20 mg (ESO). METHODS: A randomized, open-label, multiple-dose, two-treatment, two-sequence crossover study was conducted in 40 healthy male subjects. Subjects received either IR-ESO or ESO for 7 days. After single and multiple dosing, blood samples were collected for PK analysis, and intragastric pH was assessed by 24-hr pH monitoring. RESULTS: Plasma esomeprazole exposure of IR-ESO was similar to that of ESO after single and multiple dosing. Time to peak concentration of IR-ESO (0.50-0.75 hr) was shorter than that of ESO (1.25-1.50 hr). Percentage changes in 24-hr integrated gastric acidity from baseline for IR-ESO were similar to those for ESO. In addition, mean time to maintain gastric pH >4 for 24 hr was similar for both drugs (IR-ESO 55.5-69.9% vs ESO 56.8-70.2%). Evaluation of time to first reach pH 4 after dosing indicated that IR-ESO showed a faster onset than ESO. All subjects found the drug tolerable, and there were no significant differences in adverse events between two drugs. CONCLUSION: This study showed that IR-ESO produced a rapid, safe and sustained gastric acid suppression (ClinicalTrials.gov: NCT03211143).

Developing a High-Performance Liquid Chromatography (HPLC) Method for Simultaneous Determination of Oxytetracycline, Tinidazole and Esomeprazole in Human Plasma.

A high performance liquid chromatography method had been developed and validated for rapid simultaneous separation and determination of three anti-helicobacter drugs, oxytetracycline (OXY), tinidazole (TIN) and esomeprazole (ESM) in human plasma within 6 minutes. Drugs extraction method from plasma was based on protein precipitation technique. Separation was carried out on a Equisil BDS C18 column (5 µm, 150 × 4.60 mm) using a mobile phase of acetonitrile: 0.025 M KH2PO4 (25: 75, v/v) adjusted to pH 3.50 with ortho-phosphoric acid at ambient temperature. The flow rate was 1 mL/min and maximum absorption was measured using Diode Array (DAD) detector at 285 nm. The retention times of OXY, TIN and ESM were recorded to be 2.68, 3.52 and 5.17 minutes, respectively, indicating a shorter analysis time. Limits of detection were also reported to be 0.10, 0.07 and 0.04 µg/mL for OXY, TIN and ESM, respectively, showing a high degree of the method sensitivity. The method was then validated according to FDA guidelines for the determination of the drugs clinically in human plasma specially regarding pharmacokinetic and bioequivalence studies.

Influence of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib: A Randomized Crossover Pharmacokinetic Study.

Regorafenib exposure could potentially be influenced by an interaction with acid-reducing drugs. In this crossover trial, patients were randomized into two sequence groups consisting of three phases: regorafenib intake alone, regorafenib with concomitant esomeprazole, and regorafenib with esomeprazole 3 hours prior. The primary end point was the relative difference (RD) in geometric means for regorafenib 0-24-hour area under the concentration-time curve (AUC0-24h ) and was analyzed by a linear mixed model in 14 patients. AUC0-24h for regorafenib alone was 55.9 µg·hour/mL (coefficient of variance (CV): 40%), and for regorafenib with concomitant esomeprazole or with esomeprazole 3 hours prior AUC0-24h was 53.7 µg·hour/mL (CV: 34%) and 53.6 µg·hour/mL (CV: 43%), respectively. No significant differences were identified when regorafenib alone was compared with regorafenib with concomitant esomeprazole (RD: -3.9%; 95% confidence interval (CI): -20.5 to 16.1%; P = 1.0) or regorafenib with esomeprazole 3 hours prior (RD: -4.1%; 95% CI: -22.8 to 19.2%; P = 1.0). These findings indicate that regorafenib and esomeprazole can be safely combined in clinical practice.

Assessing the bioequivalence of over-the-counter esomeprazole banded capsules and multiple-unit pellet system tablets
.

OBJECTIVE: To demonstrate bioequivalence between two esomeprazole formulations under fasted and fed conditions. MATERIALS: Esomeprazole 20 mg multiunit pellet system (test; MUPS) tablets and over-the-counter esomeprazole 20 mg banded capsules (reference). MATERIALS AND METHODS: This open-label, randomized, 6-period crossover study assigned healthy males and females to receive single doses of each study drug under fasted or fed conditions. The primary pharmacokinetic endpoints were esomeprazole area under the concentration-time curve from time zero to infinity (AUCinf) and maximum observed concentration (Cmax). For endpoints with high within-subject standard deviations of the reference product (Swr ≥ 0.294), a reference scaled average bioequivalence (RSAB) approach was used. For endpoints not highly variable (Swr < 0.294), an unscaled approach was used. In the RSAB, bioequivalence was defined as the 95% criteria bound (CB) ≤ 0 and geometric mean ratios (GMRs) within 0.80, 1.25. For the unscaled approach, bioequivalence was defined as 90% confidence intervals (CIs) of the GMR being within 80%, 125%. RESULTS: 60 subjects were randomized, and 46 subjects (76.7%) completed all study periods. For esomeprazole AUCinf, the variability of the reference product was low (Swr = 0.202), so the unscaled approach was used. The GMR (90% CI) was 0.948 (0.890 - 1.010), indicating bioequivalence. For the comparison of esomeprazole Cmax, the variability of the reference product was high (Swr = 0.304), so the RSAB approach was used. The GMR (95% CB) was 1.009 (-0.050), indicating bioequivalence. CONCLUSION: Esomeprazole 20 mg MUPS tablets and banded capsules were found to be bioequivalent based on the AUCinf and Cmax in the fasted state.
.

A fast, sensitive, and high throughput method for the determination of esomeprazole in dog plasma by UHPLC-MS/MS: Application to formulation development of the compound preparation of esomeprazole.

To investigate deeply into the preclinical pharmacokinetics and prescription design of esomeprazole, a sensitive, high throughput and robust UHPLC-MS/MS method had been developed and fully validated for the analysis of esomeprazole in dog plasma. Esomeprazole and diazepam (IS) were fast extracted from plasma by alkalified organic solvent, and separated on MP-C18 column with methanol and 0.1% formic acid. The quantification of esomeprazole and IS had been achieved using fragmentation transitions of m/z 346.1→198.1 and m/z 285.0→193.2 in MRM detection under positive ESI mode. The concentration of esomeprazole in dog plasma was linear with the range of 3.75-500ng/mL. The precisions of intra- and inter-day were no more than 11.6%, while the accuracies were all within ±9.7% of the nominal values. The recovery was no more than 77.06%, and the matrix effect, stability, dilution integrity tests were all satisfied the currently criterion. Then the method was successfully performed to evaluating pharmacokinetics of esomeprazole and optimizing the prescription of modified esomeprazole with varied addition of sodium bicarbonate. Consequently, a pharmacokinetic study of three doses esomeprazole with the optimized addition of sodium bicarbonate in dogs has been successfully researched for the first time. It could be a promising approach to improve the stabilization of acid-labile esomeprazole and would provide a useful reference for the formulation design of esomeprazole.

Pharmacokinetics and Acid Suppressant Efficacy of Esomeprazole after Intravenous, Oral, and Subcutaneous Administration to Healthy Beagle Dogs.

BACKGROUND: Esomeprazole is an S-enantiomer of omeprazole that has favorable pharmacokinetics and efficacious acid suppressant properties in humans. However, the pharmacokinetics and effects on intragastric pH of esomeprazole in dogs have not been reported. OBJECTIVE: To determine the pharmacokinetics of esomeprazole administered via various routes (PK study) and to investigate the effect of esomeprazole on intragastric pH with a Bravo pH monitoring system (PD study). ANIMALS: Seven adult male Beagle dogs and 5 adult male Beagle dogs were used for PK and PD study, respectively. METHODS: Both studies used an open, randomized, and crossover design. In the PK study, 7 dogs received intravenous (IV), subcutaneous (SC), and oral doses (PO) of esomeprazole (1 mg/kg). Each treatment period was separated by a washout period of at least 10 days. Esomeprazole plasma concentrations were measured by HPLC/MS/MS. In the efficacy study, intragastric pH was recorded without medication (baseline pH) and following IV, SC, and PO esomeprazole dosing regimens (1 mg/kg) in 5 dogs. RESULTS: The bioavailability of esomeprazole administered as PO enteric-coated granules and as SC injections was 71.4 and 106%, respectively. The half-life was approximately 1 hour. Mean ± SD percent time intragastric pH was ≥3 and ≥4 was 58.9 ± 21.1% and 40.9 ± 17.3% for IV group, 75.8 ± 16.4% and 62.7 ± 17.7% for SC group, 88.2 ± 8.9% and 82.5 ± 7.7% for PO group, and 12.5 ± 3.6% and 3.7 ± 1.8% for baseline. The mean percent time with intragastric pH was ≥3 or ≥4 was significantly increased regardless of the dosing route (P < .05). CONCLUSION: The PK parameters for PO and SC esomeprazole administration were favorable, and esomeprazole significantly increased intragastric pH after IV, PO, and SC administration. IV and SC administration of esomeprazole might be useful when PO administration is not possible. No significant adverse effects were observed.

DEVELOPMENT AND VALIDATION OF FAST REVERSED-PHASE HPLC METHOD FOR ANALYSIS OF ESOMEPRAZOLE IN RABBIT PLASMA.

The present study focused to develop rapid, accurate and sensitive reversed-phase high pressure liquid chromatography method for the quantification of esomeprazole (ESO) magnesium in rabbit plasma. Chromatographic separation was achieved isocratically on a reversed-phase C,, column using simple mobile phase consisting of of methanol : acetonitrile: 0.05 M phosphate buffer, pH 7 adjusted with potassium hydroxide (45 : 10 : 45, v/v/v) at a flow rate of 1.0 mL/min and UV detection at 302 nm. The method was validated for system suitability, linearity, precision, accuracy, stability, robustness, LOD and LOQ. The described method stated good linearity over the range of 0.01 to 2.5 pg/mL (r = 0.999). The extraction recovery of esomeprazole was more than 95.3%. The method was precise with relative standard deviation < 1% with more than 90% accuracy and limit of quantification 0.0309 µg/mL. The freeze thaw stability studies indicated that the rabbit plasma samples containing esomeprazole could be stored in freezer at -20°C and handled under normal laboratory conditions without significant loss of drug. In conclusion, the developed method is simple, cost effective and reproducible, with improved sensitivity and running time of analysis.

Proton Pump Inhibitors in Cardiovascular Disease: Drug Interactions with Antiplatelet Drugs.

Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular diseases. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies suggested an interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it was reported that PPIs may also attenuate the antiplatelet effect of aspirin. This may be clinically important, because a fixed combination of aspirin and a PPI (esomeprazole) has recently been approved and because aspirin is the most widely used drug in patients with cardiovascular disease. The antiplatelet effect of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, seems less influenced by PPI co-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover, it outlines current evidence supporting or opposing drug interactions between these drugs and discusses clinical implications.

Bioanalytical method for the estimation of co-administered esomeprazole, leflunomide and ibuprofen in human plasma and in pharmaceutical dosage forms using micellar liquid chromatography.

The present study represents a connection between basic science and clinical applied science through providing a bioanalytical method for the analysis of certain co-administered drugs used for the treatment of rheumatoid arthritis. The studied drugs are esomeprazole, leflunomide and ibuprofen. The proposed bioanalytical method is a simple reversed phase high performance liquid chromatographic method using micellar mobile phase. The method is conducted using a Shim-pack VP-ODS (150 mm × 4.6 mm ID) stainless steel column at ambient temperature with ultraviolet detection at 285 nm. The micellar mobile phase consisted of 0.1 m sodium dodecyl sulfate, 10% n-propanol, 0.3% triethylamine in 0.02 m orthophosphoric acid (pH 3.5) and is pumped at a flow rate of 1.0 mL/min. The calibration curve was rectilinear over the concentration range of 0.1-5.0, 0.5-10.0 and 1.0-20.0 µg/mL for esomeprazole, leflunomide and ibuprofen respectively. The proposed method was successfully applied to the analysis of these drugs in dosage forms. The method is extended to the in-vitro, in-vivo determination of these drugs in spiked and real human plasma samples.

Development and validation of a DESI-HRMS/MS method for the fast profiling of esomeprazole and its metabolites in rat plasma: a pharmacokinetic study.

The advances in pharmaceutical development and drug discovery impose the availability of reliable high-throughput screening methods for the rapid evaluation of drug metabolism and pharmacokinetic (PK) in biological samples. Here, a desorption electrospray mass spectrometry (DESI-MS) method has been developed and validated for the PK profiling of esomeprazole and its metabolites (5-hydroxyomeprazole and omeprazole sulfone) in rat plasma. Rats were treated with an esomeprazole solution (2.5 mg/mL) for endovenous administration and the analyte levels were profiled over 2 h after liquid-liquid extraction from plasma. MS and tandem mass spectrometry (MS/MS) experiments were performed by using a DESI-LTQ-Orbitrap XL instrument and an on-spot fixed time analysis on PMMA surfaces. Validation was performed for the esomeprazole. The DESI-MS/MS method exhibited for the esomepazole excellent sensitivity (limit of detection (LOD)=60 ng/mL), linearity (0.2-20 µg/mL concentration range; y=23848(±361)X, n=15; r(2) =0.987) and precision (RSD<9%) by using an internal standard method. The PK results were discussed in terms of Area Under the Curve, Cmax and Tmax . Data reliability was demonstrated by comparison with a liquid chromatography-tandem mass spectrometry method (p>0.05). The data achieved demonstrated that the DESI-MS method is suitable for sensitive and fast profiling of a drug and its metabolites at the therapeutic concentration levels.

Comparison of the pharmacokinetics and tolerability of HCP1004 (a fixed-dose combination of naproxen and esomeprazole strontium) and VIMOVO® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium) in healthy volunteers.

BACKGROUND: HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO(®) (a marketed fixed-dose combination of naproxen and esomeprazole magnesium). SUBJECTS AND METHODS: An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO(®)) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (Cmax) and the area under the concentration-time curve from 0 to the last measurable time (AUC0-t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study. RESULTS: Sixty-six of the 70 subjects completed the study. The Cmax (mean ± standard deviation) and AUC0-t (mean ± standard deviation) for naproxen in HCP1004 were 61.67 ± 15.16 µg/mL and 1,206.52 ± 166.46 h · µg/mL, respectively; in VIMOVO(®); these values were 61.85 ± 14.54 µg/mL and 1,211.44 ± 170.01 h · µg/mL, respectively. The Cmax and AUC0-t for esomeprazole in HCP1004 were 658.21 ± 510.91 ng/mL and 1,109.11 ± 1,111.59 h · ng/mL, respectively; for VIMOVO(®), these values were 595.09 ± 364.23 ng/mL and 1,015.12 ± 952.98 h · ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO(®)) of the Cmax and AUC0-t of naproxen were 0.99 (0.94-1.06) and 1.00 (0.98-1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the Cmax and AUC0-t were 0.99 (0.82-1.18) and 1.04 (0.91-1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment. CONCLUSION: The PK of HCP1004 500/20 mg was comparable to that of VIMOVO(®) 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.

Enhanced spectrofluorimetric determination of esomeprazole and pantoprazole in dosage forms and spiked human plasma using organized media.

A simple, sensitive and rapid spectrofluorimetric method was developed for the determination of esomeprazole (EMZ) and pantoprazole (PRZ) in their pharmaceutical formulations and human plasma. The proposed method is based on the fluorescence spectral behavior of EMZ in methanol in the presence of 0.1 m NaOH containing 0.5% methyl cellulose (MC) at 306/345 nm. The fluorescence intensity of EMZ was enhanced about 1.3-fold and good linearity in the range 0.4-4.0 µg/mL with a lower detection limit of 0.04 µg/mL and lower quantification limit of 0.14 µg/mL. For PRZ, its methanolic solution exhibited marked native fluorescence at 290/325 nm after enhancement (about 2.1- or 1.4-fold) using either 0.025% sodium dodecyl sulfate (SDS) or 0.05% MC in the presence of 0.2 m borate buffer of pH 9.5. The fluorescence-concentration plots of PRZ were rectilinear over the ranges 0.2-2.0 and 0.3-3.0 µg/mL with lower detection limits of 0.02 and 0.03 µg/mL and lower quantification limits of 0.07 and 0.09 µg/mL using sodium dodecyl sulfate and MC, respectively. The method was successfully applied to the analysis of EMZ and PRZ in their commercial dosage forms and the results were in good agreement with those obtained with the comparison method. Furthermore, in a preliminary investigation, the proposed method was extended to the in vitro determination of the two drugs in spiked human plasma and the results were satisfactory.

The pharmacokinetics, pharmacodynamics and safety of oral doses of ilaprazole 10, 20 and 40 mg and esomeprazole 40 mg in healthy subjects: a randomised, open-label crossover study.

BACKGROUND: Ilaprazole, a proton pump inhibitor (PPI) currently in clinical use, may provide improved acid suppression vs. other PPIs. AIM: To compare the pharmacodynamic and pharmacokinetic profiles of ilaprazole and esomeprazole. METHODS: A phase 1, randomised, open-label, single-centre, 4-period crossover study was conducted in 40 healthy volunteers. Ilaprazole 10, 20 or 40 mg or esomeprazole 40 mg was administered once daily for 5 days with ≥5-day washout intervals. Pharmacokinetic blood samples and intragastric pH measurements were collected at scheduled timepoints for 24 h after dosing on Days 1 and 5. RESULTS: Esomeprazole 40 mg provided significantly better pH control during the initial hours (0-4 h) after a single dose, but ilaprazole (particularly 20 and 40 mg) provided significantly better pH control for the entire 24-h period and during evening and overnight hours after single and multiple doses. Increasing ilaprazole doses resulted in dose-proportional increases in peak plasma concentration and area under the plasma concentration vs. time curve following single and multiple doses. Ilaprazole was safe and generally well tolerated; an unexpectedly high incidence of allergic eye and skin reactions were observed but were not specific to any dosing regimen. Plasma gastrin concentrations did not increase proportionately with increasing ilaprazole dose. CONCLUSIONS: Ilaprazole provided significantly better pH control over 24 h and during evening and overnight hours compared with esomeprazole in healthy volunteers, which may translate to greater relief of night-time heartburn in the clinical setting for patients with gastric acid-related disorders.

Pharmacokinetics, pharmacodynamics, and safety of esomeprazole injection/infusion in healthy Chinese volunteers: a five-way crossover study.

BACKGROUND: Esomeprazole provides effective and long lasting inhibition of gastric acid secretion. However, the pharmacokinetics and pharmacodynamics of intravenous esomeprazole in the Chinese population remain unclear. AIM: To compare the pharmacokinetics and pharmacodynamics of intravenous esomeprazole (injection and infusion) and their clinical safety and tolerability in healthy Chinese subjects. METHODS: A randomized, single-center, open-label, five-way crossover study was conducted in 20 healthy volunteers. CYP2C19 metabolizer genotype and Helicobacter pylori status were examined. Five dosing regimens were used: single 40 mg injection, 40 mg infusion every 12 h, 40 mg infusion followed by continuous infusion at 8 mg/h, 80 mg infusion followed by continuous infusion at 4 or 8 mg/h. Intragastric pH was recorded within 24 h. Plasma concentration-time curve, maximum plasma concentration (Cmax ), steady state concentration, and total plasma clearance were determined. Adverse events were also recorded. RESULTS: Continuous infusion resulted in a higher mean area under the curve and Cmax than injection. There were no significant differences among the four infusion groups in terms of percentages of time at pH > 4, > 5, > 6, > 7 within 24 h and pH > 6 within the first 3 h. There were no significant differences in pharmacokinetic or pH values among variants of CYP2C19 genotype. The pH value within 24 h was unaffected by H. pylori infection in subjects with continuous infusion. CONCLUSIONS: Esomeprazole administrated by infusion produces better pharmacokinetic and intragastric pH profiles compared with those by injection. The optimal administration schedule for esomeprazole in Chinese subjects is infusion with 40 mg/12 h.

Development and validation of a sensitive and high-throughput LC-MS/MS method for the simultaneous determination of esomeprazole and naproxen in human plasma.

A sensitive and high-throughput LC-MS/MS method has been developed and validated for the combined determination of esomeprazole and naproxen in human plasma with ibuprofen as internal standard. Solid-phase extraction was used to extract both analytes and internal standard from human plasma. Chromatographic separation was achieved in 4.0 min on XBridge C18 column using acetonitrile-25 mM ammonium formate (70:30, v/v) as mobile phase. Mass detection was achieved by ESI/MS/MS in negative ion mode, monitoring at m/z 344.19 → 194.12, 229.12 → 169.05 and 205.13 → 161.07 for esomeprazole, naproxen and IS, respectively. The calibration curves were linear from 3.00 to 700.02 ng/mL for esomeprazole and 0.50 to 150.08 ng/mL for naproxen. The intra- and inter-batch precision and accuracy across four quality control levels met established criteria of US Food and Drug Administration guidelines. The assay is suitable for measuring accurate esomeprazole and naproxen plasma concentrations in human bioequivalence study following combined administration.

Changes in gastric pH and in pharmacokinetics of ulipristal acetate - a drug-drug interaction study using the proton pump inhibitor esomeprazole.

OBJECTIVE: Ulipristal acetate is a novel selective progesterone receptor modulator for the treatment of benign gynecological conditions such as uterine myoma. As a Biopharmaceutical Classification System (BCS) II compound, it is highly soluble at low pH but has low solubility at neutral conditions. Esomeprazole, a proton pump inhibitor used widely for treatment of gastric and duodenal ulcers, efficiently increases gastric pH. Thus, the aim of this study was to determine the effects of esomeprazole on the pharmacokinetics of ulipristal acetate. MATERIALS AND METHODS: This was a nonrandomized, single sequence, 2 period, open, study in 18 healthy female subjects. Subjects received oral ulipristal acetate tablets (10 mg) once on Days 1 and 13 and daily esomeprazole administrations (20 mg) from Days 9 through 14. RESULTS: Co-administration of esomeprazole decreased geometric mean Cmax of ulipristal acetate by 65% (geometric mean ratio point estimate (90% CI): 0.35 (0.28 - 0.42)), and delayed median tmax from 0.75 to 1.00 h (Hodges-Lehmann estimate of difference (90% CI): tmax 0.63 (0.25 - 1.25)) but had minor effects on AUCs of +15% and +11% (geometric mean ratio point estimates (90% CI): AUC0-t 1.15 (1.02 - 1.31) and AUC0-∞ (1.11 (0.98 - 1.27)), respectively. A total of 6 adverse events were reported by 4 subjects, none of them being serious. CONCLUSIONS: Concomitant use of ulipristal acetate with esomeprazole at therapeutic concentrations led to a modified absorption rate while exposure in terms of AUC remained close to bioequivalence limits. In the context of chronic administration of ulipristal acetate, no clinically significant effects are expected from co-administration with drugs increasing gastric pH.

Phase I, multicenter, randomized, open-label study evaluating the pharmacokinetics and safety profile of repeated once-daily doses of intravenous esomeprazole in children 0 to 17 years of age.

BACKGROUND: Several oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children. OBJECTIVE: The aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children. METHODS: In this multicenter, open-label study, hospitalized patients (0-17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0-1 month of age), 1.0 mg/kg (1-11 months of age), 10 mg (1-5 years of age), 10 or 20 mg (6-11 years of age), or 20 or 40 mg (12-17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed. RESULTS: Fifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC(τ) ranged from 6.9 µmol · h/L (10 mg, 6-11 years) to 17.6 µmol · h/L (40 mg, 12-17 years). The mean C(ss,max) ranged from 3.7 µmol/L (0.5 mg/kg, 0-1 month) to 10.5 µmol/L (40 mg, 12-17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs. CONCLUSIONS: Intravenous esomeprazole at doses resulting in targeted AUC(τ) and C(ss,max) similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019.