Co-administration Of Omeprazole Research Articles

Clinicopathologic and gastrointestinal effects of administration of prednisone, prednisone with omeprazole, or prednisone with probiotics to dogs: A double-blind randomized trial.

The efffect of administering of probiotics or twice-daily omeprazole on glucocorticoid-induced gastric bleeding in dogs is unknown. Compare gastrointestinal bleeding among dogs administered placebo, prednisone (2mg/kg q24h), prednisone with omeprazole (1mg/kg q12h), or prednisone with probiotics (Visbiome, 11.2-22.5 billion CFU/kg q24h) for 28 days. Twenty-four healthy research dogs. Double-blinded, placebo-controlled randomized trial. Clinical signs and endoscopic gastrointestinal mucosal lesion scores at baseline (t1 ), day 14 (t2 ), and day 28 (t3 ) were compared using split-plot repeated-measures mixed-model ANOVAs. Fecal score differed by treatment-by-time (F[6,40] = 2.65, P < .03), with higher scores in groups receiving prednisone at t3 than t1 . Nineteen of thirty-three episodes of diarrhea occurred in the prednisone with omeprazole group. Gastric mucosal lesion scores differed by treatment-by-time (F[6,60] = 2.86, P=.05), among treatment groups (F[3,60] = 4.9, P=.004), and over time (F[2,60] = 16.5, P < .001). Post hoc analysis revealed lesion scores increased over time for all groups receiving prednisone. At t3 , scores for the prednisone (8.7 ± 4.9) and prednisone with probiotics (8.7 ± 4.9) groups differed significantly from placebo (1.8 ± 1.8; P ≤ .04), whereas scores for the prednisone with omeprazole (6.5 ± 5.5) group did not differ from placebo (P=.7). Ulcers occurred only in dogs receiving prednisone. Prednisone-induced gastric bleeding. Co-administration of omeprazole partially mitigated bleeding, but a similar protective benefit was not demonstrated by co-administration of the evaluated probiotic.

Evaluation of the pharmacological interactions between coadministered Newbouldia laevis root bark extract and omeprazole in ulcer induced rat model

Ulcers are wounds on the lining of the gastrointestinal tract. There are different types of ulcers some of which include: duodenal, gastric and esophageal ulcers. The most common type of ulcers is peptic ulcers which occur mostly in those portions that come into contact with stomach acids and enzymes. Other causes of ulcers comprise antibiotics, anti-inflammatory drugs, alcohol and a microorganism called Helicobacter pylori. There are numerous antiulcer drugs in current use. These drugs are associated with many problems some of which are life-threatening. In other to avert these complications, herbal remedies are used recently because they are expected to be more efficacious and with high safety potentials. In this study, we evaluated the antiulcer interactions between coadministered Newbouldia laevis root bark extract and Omeprazole using rat model. The 12 mature Wister rats used in this study were divided into four groups of three rats each. Distilled water, Omeprazole, extract of Newbouldia laevis alone and coadministration of Omeprazole and Newbouldia laevis extract were given to groups I, II, III and IV respectively. After 30 minutes, ulcer was induced in all the rats using 95% ethanol. One hour later, all the rats were sacrificed and the gastrointestinal tract separated. The pH of gastrointestinal content was assessed and the number of ulcers counted. The least number of ulcers were observed in group IV. It was concluded that Newbouldia laevis and Omeprazole interacted synergistically because they, in combination, exhibited better ulcer protective effects than each of the treatments given alone.

The complete bioavailability of asundexian is unaffected by tablet formulation, gastric pH or food

Abstract Background Anticoagulation and antiplatelet therapy, mainstays for the prevention of thromboembolic disorders, are associated with an increased bleeding risk. Asundexian, a novel, potent and reversible oral inhibitor of factor XIa, is independent of the extrinsic coagulation pathway and thus not expected to increase bleeding risk. Purpose To determine the absolute bioavailability (FAB), and to assess the impact of gastric pH modulators, tablet formulation, and food on the PK and safety of asundexian. Methods Four studies enrolled healthy White males aged 18–45 years. For FAB (20463), participants received a microdose of 50 μg stable [13C7,15N]-labelled asundexian intravenously (iv) 2 hours after 25 mg asundexian orally in the fasted state. The remaining studies randomized participants to each of 3 treatment sequences. Tablet formulation and food effects were explored in studies 19663 and 21660; participants received asundexian (immediate release [IR] vs amorphous solid dispersion [ASD] phase [Ph] 2 [19663] or ASD Ph 2 vs ASD Ph 3 [21660]) in the fasted states. Food effect was explored using the Ph 2 and Ph 3 tablets. Gastric pH modulators (omeprazole and antacid) were given with asundexian in the fasted state (20459). Blood samples were taken over 72–96 hours post dose. Key PK parameters were area under concentration/time curve (AUC; and AUC/dose [D]) and maximum observed concentration (Cmax; and Cmax/D). FAB was derived as (AUC/D)oral/(AUC/D)iv. Relative bioavailability (FR) was derived from the ratios (ASD Ph 2:IR or ASD Ph 3:ASD Ph 2) of AUC/D and Cmax/D (fasted); gastric pH modulation and food effect were derived from the ratios asundexian+pH modulator:asundexian and fed:fasted of AUC and Cmax, respectively. Results PK data were available for 59 participants. Asundexian was completely bioavailable (FAB, 103.9%). Ph 2 and Ph 3 ASD tablets exhibited a FR of 94.3% and 95.1% for AUC/D compared with the IR or Ph 2 ASD tablet, respectively. Cmax/D results were similar (95.5% and 88.7%, respectively). A high-calorie, high-fat meal reduced AUC and Cmax of asundexian to 91.1% and 78.3%, respectively (ASD Ph 2 tablet), and to 96.9% and 95.1%, respectively (ASD Ph 3 tablet). Coadministration of omeprazole had no influence on the PK of asundexian, whereas antacid slightly reduced AUC and Cmax by 10% and 16%, respectively. Geometric least-squares mean (90% confidence intervals) for the ratios of AUC(/D) and Cmax(/D) by treatment are shown in Figure 1. There were no serious adverse events (AEs) or deaths; most AEs were mild or moderate. Conclusions Orally administered asundexian was almost completely bioavailable. First pass metabolism in the gut and liver does not play an important role in the bioavailability of asundexian; there were no clinically relevant changes due to formulation, food conditions or gastric pH modulation. Results were used to guide dosing recommendations for subsequent Ph 2 (completed) and Ph 3 (planned) studies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG

POS0672 FIRST-IN-HUMAN STUDY OF GS-5718, AN ORAL IRAK-4 INHIBITOR, IN HEALTHY SUBJECTS: PHARMACOKINETICS, SAFETY, TOLERABILITY, AND ASSESSMENT OF EFFECT OF FOOD AND ACID REDUCING AGENTS ON EXPOSURE

Background:GS-5718 is a potent and selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in clinical development for treatment of inflammatory diseases.Objectives:The aim of this first-in-human study was to evaluate the pharmacokinetics, safety, and tolerability of GS-5718; and the effect of food and acid-reducing agents (ARA) on GS-5718 pharmacokinetics in healthy subjects.Methods:This was a blinded, randomized, placebo-controlled, single and multiple (once daily for 10 days) oral dose study. Healthy male and female subjects were enrolled in ascending dose cohorts and randomized to receive GS-5718 (15, 50 or 150 mg) or placebo. GS-5718 was administered fasted in the single ascending dose cohorts, and under fed conditions (standard meal) in the multiple dose cohorts. The effects of a high-fat meal and omeprazole (a representative ARA) on GS-5718 50 mg dose pharmacokinetics were also evaluated. Serial blood samples were collected and GS-5718 pharmacokinetic parameters were characterized. Safety was assessed by review of adverse events (AEs), clinical laboratory tests, and vital signs.Results:A total of 74 subjects (n = 62 GS-5718; n = 12 placebo) enrolled and completed study drug treatments in this study. GS-5718 was generally well tolerated at all evaluated dose levels; AEs were mild in severity and no dose-limiting toxicities, serious AEs, nor clinically relevant electrocardiogram or vital sign abnormalities were observed in subjects administered GS-5718. GS-5718 exposure was approximately dose proportional across the evaluated multiple ascending dose range. GS-5718 showed low-to-moderate pharmacokinetic variability with median half-life of 25 to 33 hours and 1.6 to 2.4- fold accumulation at steady-state, which was achieved by Day 5-7 of dosing. Food had no clinically meaningful impact on GS-5718 exposure (AUC and Cmax) at the 50 mg dose. Co-administration of omeprazole with GS-5718 reduced GS-5718 exposure (AUC and Cmax) by 23% and 43%, respectively, at the 50 mg dose.Conclusion:GS-5718, administered once daily, was well tolerated following single or multiple dosing up to 150 mg. The pharmacokinetic and safety profile of GS-5718 support the further development in inflammatory diseases with once-daily administrations.Disclosure of Interests:Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Chia-Hsiang Hsueh Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Oksana Gurtovaya Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Anubhav Mathur Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, James Taylor Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Adrian Serone Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Ahmed A. Othman Shareholder of: Gilead Sciences, Employee of: Gilead Sciences

Use of omeprazole, the proton pump inhibitor, as a potential therapy for the capecitabine-induced hand-foot syndrome

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia (PPE), is a major side effect of capecitabine. Although the pathogenesis of HFS remains unknown, some studies suggested a potential involvement of inflammation in its pathogenesis. Proton pump inhibitors (PPIs) have been reported to have anti-inflammatory effects. In this study, we investigated the ameliorative effects of omeprazole, a PPI on capecitabine-related HFS in mice model, and a real-world database. Repeated administration of capecitabine (200 mg/kg, p.o., five times a week for 3 weeks) increased fluid content, redness, and tumor necrosis factor (TNF)-α substance of the mice hind paw. Co-administration of omeprazole (20 mg/kg, p.o., at the same schedule) significantly inhibited these changes induced by capecitabine. Moreover, based on the clinical database analysis of the Food and Drug Administration Adverse Event Reporting System, the group that has used any PPIs had a lower reporting rate of capecitabine-related PPE than the group that has not used any PPIs. (6.25% vs. 8.31%, p < 0.0001, reporting odds ratio (ROR) 0.74, 95% confidence interval (CI) 0.65–0.83). Our results suggest that omeprazole may be a potential prophylactic agent for capecitabine-induced HFS.

The Association between Co-Administration of Omeprazole and Clopidogrel and Cardiovascular Outcomes

Objective: To examine whether co-administration of clopidogrel and omeprazole affects the clinical outcomes of clopidogrel treatment. Design and Methods: A retrospective cross-sectional study of 4078 patients after a percutaneous coronary intervention and stent implantation. Seven hundred twenty-three clopidogrel-treated patients who fulfilled the inclusion criteria of the study were included: 318 treated only with clopidogrel; 405 treated with clopidogrel and omeprazole (study group). The interaction between the drugs was examined in relation to adverse clinical outcomes such as all-cause mortality, Major Adverse Cardiovascular Events (MACE) and cardiac hospitalizations during one year. Results: No significant difference was detected between the groups regarding the primary outcomes of the study. Regression models adjusted to basic characteristics and clinical variables showed a significant association between the study group and the primary outcomes through interactions with specific covariates: “all-cause mortality” through interaction with the covariate ethnicity (not-Jewish) (OR = 43.12, 95% CI 1.19-1567.8, P = 0.04), “MACE” through interaction with the covariates gender (female) and complicated angioplasty (OR= 9.36, 95% CI 2.04-42.94, P= 0.04); and “cardiac hospitalizations” through interaction with the covariates extent of artery stenosis and hypertension (OR= 2.65, 95% CI 1.043-6.76, P = 0.04). Conclusion: Addition of omeprazole to clopidogrel may be associated with increased incidence of negative clinical outcomes, including death and MACE. These findings underscore the need for conduction of prospective randomized controlled trials that will examine the association between addition of omeprazole to clopidogrel and the incidence of clinical outcomes.

Interim Cell-Free Circulating Lymphoma DNA Analysis of the Phase 2 Accept Trial

Introduction Plasma cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) genotyping in Diffuse Large B-cell Lymphoma (DLBCL) holds great promise for early detection and response prediction. DLBCL is a highly heterogenous disease with diverse tumor behaviour and outcomes, yet the delineation of poor- risk groups remains challenging. Genomically driven molecular risk stratification, using ultradeep next generation sequencing (NGS) provides a comprehensive view of the mutational landscape of lymphoma and enables ultrasensitive disease detection. Here, we present an interim analysis of ctDNA kinetics from ACCEPT, a phase Ib/II study of acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for patients with previously untreated DLBCL. Methods Plasma samples were collected at four time points, at baseline and before the second, third and final cycles of chemotherapy. Extracted cell-free DNA (cfDNA) was quantified by fluorometry, prior to undergoing library preparation and next-generation sequencing using the CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) methodology. The targeted sequencing panel covered 799 regions over 50 genes (&amp;gt;200Kb) known to be involved in lymphomagenesis. Analysis was carried out with a custom bioinformatics pipeline using error-corrected deduplication and a database of known artefacts to reduce background noise and improve sensitivity for low-level somatic variant detection. Patients were closely monitored through the study period by clinical examination and PET-CT scanning to provide objective endpoints against which the ctDNA response could be correlated. Results Fifteen patients had samples analysed for all four time points at the time of the interim analysis and were included in the study. Ten (66%) had late stage disease, nine (60%) poor risk disease (IPI &amp;gt; 2). Early vs late stage of disease at presentation showed a strong correlation with baseline levels of both total cfDNA (3,946 HGE/ml vs 21,613 HGE/ml) and ctDNA (842HGE/ml vs 6,380 HGE/ml). Twelve patients (80%) had trackable variants detected at baseline. The majority of these cleared after the first cycle of chemotherapy (Figure A; representative patient). Two cases (Figures B and C) had variants persistently detectable at high variant allele frequency (VAF) (0.059 and 0.068). These patients both had primary refractory disease. One patient from the first acalabrutinib dose escalation cohort and the second patient was found to be ineligible and withdrawn from the primary analysis because of continuous co-administration of omeprazole during therapy which inhibits acalabrutinib absorption. All others achieved a metabolic complete metabolic remission (mCR) after the final cycle of therapy. A third pattern of response noted was (Figure D) showing disappearance of detectable variants at baseline but progressive emergence of an acquired TP53 variant throughout follow-up that was not detected in the patient's germline sample. This high-risk patient with IPI of 5 and triple-hit DLBCL achieved a mCR and remains in remission in follow-up. Conclusion The clearance of ctDNA from the plasma of the responding patients in our study is consistent with the prior literature, as is the poor prognostic significance of persisting variants after the first cycle of chemotherapy. The rapid kinetics of the changes in ctDNA is noted and is potentially of advantage over other modalities of monitoring, such as PET-CT scan. Data on the entire cohort (n=30) and longer follow-up will be available at the time of the meeting. Figure 1 Disclosures Davies: Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Johnson:Oncimmune: Consultancy; Bristol-Myers: Honoraria; Celgene: Honoraria; Genmab: Honoraria; Incyte: Honoraria; Kite Pharma: Honoraria; Kymera: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Boehringer Ingelheim: Consultancy; Epizyme: Consultancy, Research Funding; Janssen: Consultancy; Oncimmune: Consultancy; Epizyme: Consultancy, Research Funding; Janssen: Consultancy. Schuh:Illumina: Other: Consulting fees; Roche: Other: Consulting fees; Gilead: Other: Consulting fees; Abbvie: Other: Consulting fees.

Antioxidant protection enzyme activity in the blood serum and large intestinal mucosa of rats with prolonged gastric hypochlorhydria and given multiprobiotics

The activity of antioxidant protection enzymes in the blood serum and colon mucosa in rats was studied under the conditions of 28-days administration of omeprazole on its own and omeprazole together with multiprobiotics "Symbiter" and "Apibact". Physiological and biochemical study methods were applied. It was found that after omeprazole administration, the activity of superoxide dismutase in the blood serum decreased, and the activity of catalase increased compared to the control. With the co-administration of omeprazole and multiprobiotics, the activity of superoxide dismutase increased compared to the group of rats that received omeprazole only during the same time, but remained less compared to the control group. The content of reduced glutathione in the blood serum of rats after administration of omeprazole decreased, the activity of glutathione peroxidase and glutathione transferase increased, and the activity of glutathione reductase decreased compared to the control. With co-administration of omeprazole and multiprobiotics, the serum RG content was at the control level, the activity of glutathione reductase exceeded the control values. The activity of glutathione reductase decreased compared to the group receiving omeprazole only. The activity of glutathione reductase increased and did not differ from the control values. In the colon mucosa, superoxide dismutase and catalase activity decreased compared to control. With the combined administration of omeprazole and multiprobiotics, superoxide dismutase and catalase activity increased and even exceeded the control values. With the administration of omeprazole, the reduced glutathione content in the colon mucosa was lower than that in the control. The activity of glutathione peroxidase increased and glutathione transferase and activity of glutathione reductase decreased compared to the control. With co-administration of omeprazole and multiprobiotics to rats, the reduced glutathione content increased compared to the group of rats administered omeprazole only, and even exceeded that in the control.

Pharmacokinetic Interaction Study Between Saxagliptin and Omeprazole, Famotidine, or Magnesium and Aluminum Hydroxides Plus Simethicone in Healthy Subjects: An Open-Label Randomized Crossover Study.

Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Mean Cmax of saxagliptin was 26% lower, but AUC was almost unchanged when saxagliptin was coadministered with Maalox Max. Mean Cmax was 14% higher, but AUC was almost unchanged when saxagliptin was coadministered with famotidine. Changes in pharmacokinetics of 5-hydroxy saxagliptin generally paralleled the changes in saxagliptin. These pharmacokinetic changes were unlikely to be clinically meaningful. Coadministration of omeprazole did not affect saxagliptin Cmax or AUC. Saxagliptin in combination with these medicines resulted in no unexpected safety or tolerability findings in these healthy subjects. No dose adjustment of saxagliptin or separation in the time of saxagliptin dosing is necessary with medicines that raise gastric pH when coadministered with saxagliptin.

PPIs may decrease the effectiveness of hepatitis C antivirals

Sustained virologic responses (SVRs) were lower in patients with hepatitis C taking direct-acting antivirals with proton pump inhibitors (PPIs) compared with those not receiving PPIs, according to results of a comprehensive review published in the Journal of Clinical and Translational Hepatology. Acid-reducing medications have been shown to decrease the concentrations of select hepatitis C treatments such as ledipasvir/sofosbuvir (Harvoni—Gilead) and sofosbuvir/velpatasvir (Epclusa—Gilead). However, previous research about the effects of concurrent use of PPIs and direct-acting antivirals on SVRs in patients with hepatitis C has been inconsistent. A systematic review and meta-analysis were conducted to assess the effects of PPIs on SVRs in patients with hepatitis C receiving a variety of direct-acting antivirals. Nine cohort studies involving 32,684 patients were included in the analysis. Seven of these nine studies assessed the interaction between PPIs and ledipasvir/sofosbuvir. The analysis showed that there were lower odds of achieving an SVR in patients who were on concurrent PPIs compared with those not on PPI therapy. A similar trend was observed for achieving an SVR at 12 weeks. The results remained the same even after adjusting for select confounding factors. The authors of the current analysis concluded that the study “demonstrated a significantly increased risk of failure of achievement of SVR in [hepatitis C virus]–infected patients taking [direct-acting antivirals] with PPIs compared to non-PPI users. Providers should consider whether PPI therapy is indicated for these patients and withdraw PPI therapy in the absence of indications.” An assessment of the labels for various direct-acting antivirals showed that they include cautions on potential drug interactions with PPIs. For example, the prescribing information for ledipasvir/sofosbuvir noted that the solubility of ledipasvir decreases as gastric pH increases. Therefore, drugs such as antacids, histamine-2 receptor antagonists, and PPIs that increase gastric pH are expected to decrease the concentration of ledipasvir. The label recommends that doses comparable to omeprazole 20 mg or lower can be administered simultaneously with the drug under fasting conditions. A similar statement is listed in the sofosbuvir/velpatasvir prescribing information, in which the solubility of velpatasvir decreases as gastric pH increases. The label states that coadministration of omeprazole or other PPIs is not recommended, but if it is medically necessary, the direct-acting antiviral should be administered with food and taken 4 hours before omeprazole 20 mg. Inform patients with hepatitis C receiving direct-acting antivirals about the potential for these agents to interact with PPIs. Tell them to avoid PPIs (both OTC and prescription agents) unless their prescriber deems them to be medically necessary.

COMPARATIVE STUDY BETWEEN THE EFFECT OF HISTAMINE RECEPTOR ANTAGONISTS OF TYPE II (FAMOTIDINE) AND PROTON PUMP INHIBITORS (OMEPRAZOLE) ON THE EFFICACY OF CALCIUM CARBONATE AS PHOSPHATE BINDER IN HAEMODIALYSIS PATIENT

Objective: The purpose of this study was to compare the effect of famotidine versus omeprazole on the efficacy of calcium carbonate as a phosphate binder in the hemodialysis patient.Methods: From February 2014 to June 2014 a total number of 64 patients of both sexes were recruited from the department of renal dialysis, Tanta University Hospital, Egypt. Patients categorized into 3 groups. Group I (control group) consisted of 20 Patients (10) females and (10) males take calcium carbonate (caco3) (2.5–4 g/d) only, Group II consisted of 21 Patients (13) females and (8) males take the same dose of caco3 with famotidine 10 mg/d and Group III consisted of 23 Patients (8) females and (15) male take the same dose caco3 with omeprazole 20 mg/d.Results: All data are expressed as the mean±SD. Group II showed a significant increase (p&lt;0.05) in serum phosphorus at 3rd mo with significant decreased (p&lt;0.05) in serum calcium comparing with pre-treatment. Group III showed no significant change (p&gt;0.05) in serum calcium, phosphorus and parathyroid hormone (PTH) comparing with pre-treatment. Both groups (II and III) showed a significant decrease in alkaline phosphatase (ALP) (p&lt;0.05).Conclusion: Co-administration of famotidine with calcium carbonate aggravates hyperphosphatemia and this may increase the incidence of complications. The efficacy of calcium carbonate as a phosphate binder was not affected by co-administration of omeprazole.

Dose optimisation of voriconazole with therapeutic drug monitoring in children: a single-centre experience in China

The pharmacokinetic profile of voriconazole is highly variable, rendering inconsistent and/or inadequate dosing, especially in children <2 years old. A retrospective analysis was performed in children receiving voriconazole with at least one plasma trough level (Ctrough) monitored. Statistical analyses were performed to examine the dose–exposure relationship as well as other factors potentially affecting voriconazole Ctrough in children of different ages. A total of 107 paediatric patients were included, of whom 75 were <2 years old. The voriconazole Ctrough was highly variable in patients aged <2 years and those aged 2–12 years. Only 47.7% of children reached the therapeutic target of 1.0–5.5 mg/L at initial dosing, whereas 48.6% of Ctrough values were subtherapeutic and 3.7% were supratherapeutic. The mean maintenance dose to reach an adequate Ctrough was 5.9 mg/kg compared with 5.1 mg/kg, resulting in insufficient levels (P = 0.005) in children aged <2 years. In this age group, the 5 to <7 mg/kg dose range significantly increased the chance of reaching the therapeutic target compared with the 3 to <5 mg/kg dose range (56.7% vs. 25.8%; P = 0.014). Overall, factors such as sex, age, liver function, renal function and co-administered medications explained only 15.9% of variability in voriconazole exposure. Co-administration of omeprazole significantly increased the voriconazole level (P = 0.032), likely through CYP2C19 inhibition. This is the largest series to date describing voriconazole dose–exposure relationships in children aged <2 years. A starting maintenance dose of 5 to <7 mg/kg intravenously twice daily may be required for most children of Asian origin to reach the therapeutic target.

An Open-Label, Sequential-Design Drug Interaction Study of the Effects of Omeprazole on the Pharmacokinetics of Ibrutinib in Healthy Adults

Background: Ibrutinib, a potent irreversible inhibitor of Bruton’s tyrosine kinase, is approved for the treatment of patients with mantle cell lymphoma (who have failed at least one prior therapy), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; including patients with 17p deletion), or Waldenström’s macroglobulinemia. Ibrutinib exhibits pH-dependent solubility (insoluble at pH ≥ 3); therefore, pH-altering agents that increase gastric pH may have the potential to impact the pharmacokinetics (PK) of ibrutinib. Physiologically-based PK modeling and simulation suggested that an increase in gastric pH would minimally impact the bioavailability of ibrutinib. To evaluate potential drug interactions between ibrutinib and pH-altering agents, a phase 1 clinical study of the effect of omeprazole, a proton pump inhibitor (PPI), on the PK of ibrutinib in healthy adults was conducted.Methods: An open-label, sequential-design drug interaction study of omeprazole coadministered with ibrutinib was conducted in healthy adults (18-55 years, inclusive). Key inclusion criteria included healthy men and women of non-childbearing potential, body mass index between 18 and 30 kg/m2, inclusive, and body weight ≥ 50 kg. On day 1, a single dose of ibrutinib (560 mg) was administered alone after an overnight fast. On days 3-6, omeprazole (40 mg) was administered alone 1 hr before breakfast. On day 7, omeprazole was administered after an overnight fast, and a single dose of ibrutinib was administered 2 hr after the omeprazole dose. Water was allowed ad libitum beginning 2 hr after ibrutinib dosing, and lunch was served ~4 hr after ibrutinib dosing.Serial PK blood samples were collected over 48 hr following dosing on days 1 and 7. Key PK parameters for ibrutinib and its metabolite (PCI-45227) were summarized for each treatment. The effect of omeprazole was determined by assessing geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC). Safety and tolerability were evaluated throughout the study.Results:Twenty healthy adults (95% men) completed the study; the median age was 48 yr and median body mass index was 25.8 kg/m2. The mean plasma concentration-time profile for ibrutinib is presented in Figures 1 and 2. AUC up to the last measurable concentration (AUClast) was similar for ibrutinib alone and in combination with omeprazole (GMR [90% CI] = 92.5%; [66.5 - 128.7]). Similar results were observed for AUC from time 0 to 48 hr (AUC48hr).Cmax of ibrutinib alone was higher than that observed when ibrutinib was coadministered with omeprazole (39.5 vs. 14.8 ng/mL, respectively; GMR (90% CI) = 37.5% (25.1 - 56.0). Median time to maximum concentration (tmax) was longer with ibrutinib plus omeprazole (2.0 hr) than with ibrutinib alone (1.0 hr). A similar reduction in Cmax and delay in tmax was observed for PCI-45227; mean AUC of PCI-45227 was approximately 20% higher when ibrutinib was administered alone than when coadministered with omeprazole.Whereas Cmax values were lower when ibrutinib was coadministered with omeprazole, the mean effect of omeprazole on AUC was minimal (<10%), albeit with a large CI. The AUC results were consistent with a population PK analysis which demonstrated that with the exception of a longer duration of absorption, coadministration of ibrutinib and antacids (mainly PPIs) under non-fasted conditions had no effect on PK parameters (Marostica E et al., Cancer Chemother Pharmacol 2015; 75:111-121). It should be noted that the effect of omeprazole coadministration on ibrutinib Cmax may be less pronounced under non-fasted conditions: because food intake itself increases gastric pH, dissolution and/or precipitation of ibrutinib in the stomach and intestinal tract would be similar for test and reference treatments.The most commonly reported treatment-emergent adverse events (AEs) were back pain (3/20; 15%), headache (2/20; 10%), abdominal pain (2/20; 10%), and diarrhea (2/20; 10%), which were all grade 1 in severity. No serious AEs were reported.Conclusions: Coadministration of omeprazole with ibrutinib decreased Cmax while marginally affecting AUC in healthy adults. Because AUC is deemed most relevant for ibrutinib's activity, coadministration of PPIs and other pH-altering agents with ibrutinib is not considered to have a clinically relevant effect on ibrutinib exposure. [Display omitted] [Display omitted] Disclosuresde Jong:Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. Jiao:Janssen: Employment. Sukbuntherng:Pharmacyclics, LLC: Employment, Equity Ownership; Global Blood Therapeutics: Equity Ownership. Ouellet:Janssen: Employment.

Omeprazole Alleviates Aristolochia manshuriensis Kom-Induced Acute Nephrotoxicity.

Aristolochia manshuriensis Kom (AMK) is a member of the Aristolochiaceae family and is a well-known cause of aristolochic acid (AA) nephropathy. In this study, we investigated the potential of omeprazole (OM) to alleviate AMK-induced nephrotoxicity. We found that OM reduced mouse mortality caused by AMK and attenuated AMK-induced acute nephrotoxicity in rats. OM enhanced hepatic Cyp 1a1/2 and renal Cyp 1a1 expression in rats, as well as CYP 1A1 expression in human renal tubular epithelial cells (HKCs). HKCs with ectopic CYP 1A1 expression were more tolerant to AA than the control cells. Therefore, OM may alleviate AMK-mediated acute nephrotoxicity through induction of CYP 1A1. We suggest that the coadministration of OM might be beneficial for reducing of AA-induced nephrotoxicity.

Effect of a Combination of Omeprazole Plus Sustained Release Baclofen Versus Omeprazole Alone on Symptoms of Patients with Gastroesophageal Reflux Disease (GERD).

Previous studies have reported the efficacy of baclofen in the treatment of Gastroesophageal Reflux Diseases (GERD). The objective of present study is to evaluate the effect of co-administration of omeprazole 20 mg/d plus sustained Release baclofen (SR baclofen) vs. omeprazole 20 mg/d plus placebo on alleviation of symptoms in patients with a diagnosis of GERD. A prospective, double blind, placebo controlled trial included 60 patients with diagnosis of GERD have been done. Patients were randomly selected to receive either SR baclofen or a placebo in addition to omeprazole 20 mg/d for a period of 2 weeks. Patients were questioned regarding heartburn, regurgitation, chest pain and hoarseness at the base line and after 2 weeks. All patients tolerated the medications and no patients failed to complete the study due to adverse drug reactions. A total of 53 patients completed the study, 25 in SR baclofen and 28 in placebo group. After 2 weeks, 1 patient (4%) in SR baclofen group reported heartburn and regurgitation. However 13(46.4%) and 15 (53.6%) of patients in the placebo group had heartburn and regurgitation respectively. The analysis of the data shows that there is a significant difference between the two groups in heartburn and regurgitation (p < 0.0001, p < 0.0001 respectively). Statistical analysis revealed a significant difference in two groups regarding total GERD score (p <0.0001). The results of the present study suggest that a combination of SR baclofen and omeprazole may be a more effective treatment for heartburn and regurgitation than omeprazole alone.

Evaluation of two Japanese regulatory actions using medical information databases: a ‘Dear Doctor’ letter to restrict oseltamivir use in teenagers, and label change caution against co-administration of omeprazole with clopidogrel

The implementation of appropriate epidemiological methodology using medical information databases (MIDs) to evaluate the effects of regulatory actions has been highly anticipated. To assess scientific methods for active pharmacovigilance using MIDs, we conducted a quantitative assessment of the impact of two regulatory actions by the Japanese government: (i) restriction of use of oseltamivir in teenagers in March 2007 and (ii) caution against the co-administration of omeprazole (OPZ) with clopidogrel (CPG) in April 2010. Data were obtained from four hub hospitals in Japan. We measured the seasonal proportion of patients prescribed oseltamivir to those prescribed neuraminidase inhibitors for the 2002/2003 to 2010/2011 seasons. The monthly proportion of patients co-administered OPZ and CPG (OPZ+CPG) to those prescribed CPG was measured from May 2009 to April 2011. We evaluated the changes observed with implementation of the regulatory actions. To estimate the impact of the actions, we conducted segmented regression analysis using interrupted time series data. The impact was assessed by two parameter estimates of the regression model: the change in level for short-term effects and change in trend for long-term effects. The use of oseltamivir in the target 10-19years age group showed a significant and large decline (63·16%) immediately after the intervention (P=0·0008). No change was observed in OPZ+CPG, although there was a relative inhibitory trend for OPZ+CPG compared with co-administration of lansoprazole or rabeprazole with CPG as the control group. When restricted to new users of CPG, the stratified results were consistent with the overall results. The current analysis demonstrates the effectiveness of two regulatory actions. The results of the current study indicate that MID research can contribute to assessing and improving pharmacovigilance activities.

Metabolomic analysis of the effects of omeprazole and famotidine on aspirin-induced gastric injury

Gastric mucosal ulceration and gastric hemorrhage are frequently associated with treatment by non-steroid anti-inflammatory drugs (NSAIDs); however, no convenient biomarker-based diagnostic methods for these adverse reactions are currently available, requiring the use of endoscopic evaluation. We recently reported five biomarker candidates in serum which predict gastric injury induced by NSAIDs in rats, but were unable to clarify the mechanism of change in the levels of these biomarker candidates. In this study, we performed capillary electrophoresis–mass spectrometry-based metabolomic profiling in stomach and serum from rats in which gastric ulcer was induced by aspirin and prevented by co-administration of omeprazole and famotidine. Results showed drug-induced decreases in the levels of citrate, cis-aconitate, succinate, 3-hydroxy butanoic acid, and O-acetyl carnitine in all animals administered aspirin. In contrast, aspirin-induced decreases in the level of 4-hydroxyproline were suppressed by co-administration of omeprazole and famotidine. We consider that these changes were due to the prevention of gastric ulcer and decrease in the amount of collagen in stomach tissue by omeprazole and famotidine, without prevention of the NSAID-induced depression of mitochondrial function. In addition, the decreases in 4-hydroxyproline in the stomach was also detectable as changes in the serum. While further study is needed to clarify limitations of indications and extrapolation to humans, this new serum biomarker candidate of gastric injury may be useful in the monitoring of NSAID-induced tissue damage.

Delayed Elimination of High Dose Methotrexate due to Co-Administration of Omeprazole: A Case Report

Methotrexate High Doses (HD-MTX) is indicated for the treatment of cancer diseases and its use requires strict precautions to prevent toxic side effects. It has also numerous drug interactions, the most known are interaction with trimethoprim - sulfamethoxazole (TMP-SMX) and Non Steroidal Anti-Inflammatory drugs (NSAIDs), which can exacerbate toxicity of MTX. We report herein a case of delayed elimination of HD-MTX due to co-administraion of omeprazole. B.A, a 17-year-old female having acute lymphoblastic leukemia (ALL). She is treated since September 2011 by HD-MTX every month for 6 months. The elimination of MTX was usually averaged at H 72 . Because of epigastralgia, the sixth cycle of HD-MTX was associated this time to omeprazole 20 mg / d during the entire cycle. MTX monitoring showed a high concentration at H 36 (23 µ mol/L) and a delayed elimination. In fact, MTX remained above 0.2 µ mol / L until H 164 . The patient ’ s serum creatinin was normal but the liver function was altered marked by transaminases increase observed at H 48 (AST = 2N, ALT = 5N). Delayed elimination of MTX was not observed in every patient receiving PPIs and the reason remains unclear. Mechanisms may include the H +/ K + ATPase pump. It seems also that inhibition of renal transporters of MTX is involved in this interaction. Genetic factors may be associated with an accentuated risk of toxicity. Because of the severity of this type of drug interaction and the frequent ambulatory use of PPIs, it is important to mention such drug-drug interaction and to find an alternative for omeprazole during HD-MTX cycles. doi: http://dx.doi.org/10.4021/jh71w

Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and β-naphthoflavone

Omeprazole (OPZ) and β-naphthoflavone (BNF) are cytochrome P450 (CYP)1A inducers and have liver tumor promoting effects. In this study, we investigated the co-promoting and co-initiating effects of OPZ and BNF in rats. In Experiment 1, male rats were subjected to partial hepatectomy (PH), and given oral doses of 138 or 276 mg/kg OPZ, 0.125% or 0.25% BNF or 138 mg/kg OPZ+0.125% BNF (n = 9~12) for 6 weeks after N-diethylnitrosamine (DEN) initiation. In Experiment 2, male rats were treated with oral doses of 138 or 276 mg/kg OPZ, 0.03% or 0.06% BNF or 138 mg/kg OPZ+0.03% BNF (n = 11~12) for 9 days starting 1 week before initiating treatment. As an initiating treatment, 2-Amino-3,4-dimethylimidazo[4,5-f]quinolone (MeIQx) was orally administered 12 hr after PH. The rats were fed a basal diet for 15 days, followed by a diet containing 0.015% 2-acetylaminofluorene for the next 10 days with a single oral dose of carbon tetrachloride. In Experiment 1, the number and area of glutathione S-transferase placental form-positive foci in the OPZ+BNF group were significantly higher than the average values of the High OPZ or the High BNF group. The expression of cyclooxygenase-2 (Cox-2) and COX-2 protein in the liver significantly increased in the OPZ+BNF group. In Experiment 2, liver initiation activity was not enhanced by the co-administration of OPZ+BNF. The results of our studies suggest that the co-administration of OPZ and BNF results in synergistic effects in the liver tumor promotion probably owing to increased COX-2 expression, but no modifying effect in the liver initiation activity of MeIQx in rats.

Effect of pH on the Stability of Amoxycillin in Buffered Aqueous Solutions and in Gastric Juice

Helicobacter pylori is associated with gastritis and peptic ulcer. The organism is susceptible to amoxycillin and many other antibiotics in-vitro. Unless administered with omeprazole, amoxycillin is ineffective in eradicating H. pylori infection. To investigate the effect of instability of amoxycillin in the failure to eradicate the organism in-vivo, the effect of pH on the stability of amoxycillin in buffered aqueous solutions and gastric juice was studied using HPLC analysis. The gastric juice was obtained from H. pylori-negative volunteers before and after they had received a seven-day course of omeprazole. Amoxycillin was most stable in aqueous solutions of pH 4 to 7. The t 1/2 in the aqueous solutions of pH 2 and 7 were 19·0 ± 0·2 and 153·1 ± 3·3 h, respectively. The t 1/2 in the gastric juice samples of pH 2 was 15·2 ± 0·3 h. At pH 7, the t 1/2 values of amoxycillin in the gastric juice samples collected from volunteers before and after the seven-day course of omeprazole were 167·0 ± 79·2 and 68·1 ± 42·3 h, respectively. The co-administration of omeprazole during treatment of H. pylori with amoxycillin is likely to increase the stability of amoxycillin in the stomach. However, amoxycillin is sufficiently stable at normal gastric pH to maintain its therapeutic efficacy in treating H. pylori infections when given alone.