The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.

BACKGROUND AND OBJECTIVES: Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of  cytochrome P450 (CYP) 3A4 and P-glycoprotein involvement. METHODS: The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4 (rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg). RESULTS: Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30 µM. Additionally, both omeprazole and rabeprazole (10 µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasma concentration) Cmax and area under the plasma concentration-time curve (AUC0-24 h), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC0-24 h. CONCLUSION: The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.

13-Week Repeated Oral Toxicity and Toxicokinetic Studies of Rabeprazole Sodium and Sodium Bicarbonate Combination in Dogs.

The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUClast and Cmax at Day 91) was greater in males than females, suggesting sex differences. AUClast and Cmax at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed Tmax and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.

Improved quantitative determination of (R)- and (S)-rabeprazole sodium and its metabolites in rat plasma by LC-MS/MS and its application to a toxicokinetic study.

There exist two enantiomers: (R)- and (S)-rabeprazole. (R)-rabeprazole offers specific pharmacokinetic advantages and enhanced therapeutic efficacy, warranting further investigation and development. Here, we developed a simple and rapid chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to simultaneously quantify rabeprazole enantiomers and their metabolites (rabeprazole sulfoxide and desmethyl rabeprazole enantiomers) and a LC-MS to quantify rabeprazole thioether. As for the chiral LC-MS/MS method, Chiral-AGP column (150 × 4 mm, 5 µm) was used and its mobile phase was acetonitrile (mobile phase A) and 10 mmol/L ammonium acetate (mobile phase B) (linear gradient profile: 0 min, 10 % B; 5 min, 15 % B; 9 min, 15 % B; 9.01 min, 10 % B; 13 min, 10 % B). The multiple reactions monitoring transitions of m/z 360.3 â†’ 242.1, 376.2 â†’ 240.1, 346.2 â†’ 228.2 and 368.2 â†’ 190.2 were opted for quantifying rabeprazole enantiomers, rabeprazole sulfoxide, desmethyl rabeprazole enantiomers and internal standard omeprazole. The analyte samples were prepared by a simple liquid-liquid extraction method. As for the LC-MS method, analytes were separated on a Inertsil® ODS-3 column (4.6 × 150 mm, 5 µm). The mobile phase was acetonitrile-5 mmol/L ammonium acetate water solution (65:35, v/v). ESI+ was used and ion peaks with m/z 344.2 (rabeprazole thioether) and 285.1 (internal standard diazepam) were monitored. Both these 2 methods were validated for specificity, linearity, precision, accuracy, matrix effect and extraction recovery, and, particularly, the stability of analytes under various conditions. We successfully applied these methods to a 13-week toxicokinetic study of rabeprazole in rats after intravenous administration of (R)- (80, 20, 5 mg/kg/d) and racemic (80 mg/kg/d) rabeprazole sodium. The results showed that rabeprazole and its metabolites did not accumulate in rats. However, desmethyl rabeprazole and rabeprazole thioether showed higher exposure and lower clearance rate in the last administration than in the first one. (R)-rabeprazole showed a higher exposure and a slower elimination rate than (S)-rabeprazole in rats. These findings offer experimental evidence and a theoretical foundation for further preclinical investigations and clinical applications of (R)-rabeprazole.

The effect of food and acid-reducing agents on the pharmacokinetic profile of capivasertib: Results from a randomized, crossover study.

AIMS: This two-part, adaptive study assessed the effect of food and an acid-reducing agent (rabeprazole) on the pharmacokinetics (PK) and safety of capivasertib, a potent AKT inhibitor, in clinical development for cancer treatment. METHODS: In Part 1, healthy participants (n = 24) were randomized to receive single-dose capivasertib after overnight fasting, a high-fat, high-calorie meal and with rabeprazole postovernight fasting in one of six treatment sequences. Based on Part 1 results, a new group of participants (n = 24) were randomized (Part 2) to receive capivasertib after overnight fasting, a low-fat, low-calorie meal and modified fasting (food restricted from 2 h before dosing to 1 h postdose) in one of six treatment sequences. Blood samples were collected for PK analyses. RESULTS: Following a high-fat, high-calorie meal, capivasertib exposure increased versus overnight fasting (geometric mean ratio [GMR] [90% confidence interval (CI)]: area under the concentration-time curve [AUCinf ] 1.32 [1.22, 1.43], maximum concentration [Cmax ] 1.23 [1.08, 1.41]), but was comparable to that postmodified fasting (GMR: AUCinf 1.13 [0.99, 1.29], Cmax 0.85 [0.70, 1.04]). AUCinf was similar and Cmax was lower with/without rabeprazole (GMR: AUCinf 0.94 [0.87, 1.02]), Cmax 0.73 [0.64, 0.84]). Capivasertib exposure was similar after a low-fat, low-calorie meal versus overnight fasting (GMR: AUCinf 1.14 [1.05, 1.25], Cmax 1.21 [0.99, 1.48]) or modified fasting (GMR: AUCinf 0.96 [0.88, 1.05], Cmax 0.86 [0.70, 1.06]). Safety was consistent with that in larger trials. CONCLUSIONS: This study demonstrates that administering capivasertib with food or acid-reducing agents does not lead to clinically relevant PK or safety profile changes.

Does Rabeprazole Sodium Alleviate the Anti-diabetic Activity of Linagliptin? Drug-Drug Interaction Analysis by In vitro and In vivo Methods.

Drug interaction has turned into the preeminent regarding issues for a prescriber during polypharmacy. The foremost objective of this research was to form a complex between linagliptin and rabeprazole sodium by in vitro interactions. The interactions between the drugs have been examined by monitoring some chromatographic and spectroscopic analyses viz. TLC, HPLC, FT-IR, UV, Job's plot, conductometric titrations, and Ardon's spectrophotometric strategy. Rabeprazole sodium formed a stable complex with linagliptin, which was ensured from the insight of these analytical data. The developed complex's bright spot was clearly watched in the TLC plate. The retention time (Rt) of the formed complex was 5.303 min, where the Rt were 3.364 and 3.103 min for linagliptin and rabeprazole sodium, respectively, in HPLC chromatograms. In FT-IR and UV spectra of the formed complex revealed some disappearance of characteristic peaks that affirmed the complexation. All of the variations of the spectrophotometric and chromatographic properties from the antecedent drugs indicated the drug-drug interaction. Another crucial fact for the experimental aim was to affirm the assumed drug interaction by in vivo model examination. The assessment of anti-diabetic property on alloxan-induced Swiss albino mice proved significant in vivo interaction between the drugs. It was outlined from the animal study that the hypoglycemic activity of linagliptin might be significantly affected due to the complex formation of the drug with a proton pump inhibitor (PPI). Nonetheless, it is the primary outcome of the interaction, which recommends the bigger in vivo study or clinical monitoring on the human model.

Effect of food on the pharmacokinetics of omeprazole, pantoprazole and rabeprazole.

BACKGROUND: The pharmacokinetics of proton pump inhibitors (PPIs) may be affected by food intake. We aimed to evaluate the effect of food on the pharmacokinetics of omeprazole, rabeprazole, and pantoprazole. SETTING: The study population comprised 186 healthy volunteers participating in 6 bioequivalence clinical trials. METHOD: Subjects were evaluated to determine the effect of a high-fat breakfast on the pharmacokinetics of omeprazole (n = 36), rabeprazole (n = 69), and pantoprazole (n = 81). MAIN OUTCOME MEASURE: Drug plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS: Food affected the pharmacokinetics of omeprazole (increased Tmax and decreased AUC and Cmax), pantoprazole (increased Tmax and decreased AUC), and rabeprazole (increased Tmax, Cmax and half-life). Food increased variability in Tmax for all 3 drugs, delaying absorption around 3 to 4 h and until 20 h in some subjects. CONCLUSION: As food delays the absorption of PPIs and increases their variability, it would be better to administer these drugs under fasting conditions. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database: EudraCT : 2004-003863-59 (registration date 05/MAR/2004), EudraCT 2006-001162-17 (registration date 17-MAR-2006), EudraCT: 2007-002489-37 (registration date 12-JUN-2007), EudraCT: 2007-002490-31 (registration date 12-JUN-2007), EudraCT: 2010-024029-19 (registration date 23-NOV-2010).

The study of intestinal absorption and biodistribution in vivo of proton pump inhibitors.

The major therapeutic strategy for acid-related gastrointestinal diseases in clinic is to reduce the excretion of gastric acid by oral administration of proton-pump inhibitors (PPIs). However, it is quite a challenge to study the oral absorption behaviors of PPIs considering their extreme instability under gastrointestinal environment. As a result, little information has been reported on PPI oral absorption so far, hindering the further development of PPI-contained oral preparations. Here, we first investigated the degradation rate of three representative PPIs, including ilaprazole, ilaprazole sodium and rabeprazole sodium. Then a modified in situ intestine absorption method in rat was established: through the temperature control by the heat exchangers, the perfusate was kept at physiological temperature only when passing through the intestine while it was maintained at 4 °C outside the intestine. Therefore PPIs could maintained sufficiently high stability under proper temperature control. Our data demonstrated that both ilaprazole and ilaprazole sodium exhibited significantly higher absorption efficiency than rabeprazole sodium did through the comparison of their apparent permeability coefficients and steady-state plasma concentrations after perfusion in the duodenum, jejunum, ileum and colon, mainly attributing to their more suitable oil-water partition coefficient. The duodenum could be the best site for the oral absorption of PPIs. Ilaprazole outperformed its sodium salt form with its stable absorption behavior in tested four intestinal segments. Furthermore, after intravenous or oral administration, ilaprazole exhibited a longer residence time and a higher accumulation in the stomach than in most of other tissues/organs. However, it was also found that the accumulation was heterogeneous and mainly located in mucosa cells of the stomach. Our further study indicated that there was no significant difference on the oral absorption efficiency of ilaprazole between female and male rats but ilaprazole underwent a faster metabolism in male rats after oral absorption. Our study provided a valuable guidance for the design of oral formulation and the optimization of PPI-contained formulations.

Bioequivalence of a Newly Developed Dabigatran Etexilate Tablet Versus the Commercial Capsule and Impact of Rabeprazole-Induced Elevated Gastric pH on Exposure in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Dabigatran etexilate (DE) is an anticoagulant with proven efficacy and tolerability for stroke prevention in patients with non-valvular atrial fibrillation. For the commercial capsule, a complex formulation is used to maintain the acidic microenvironment required for maximal absorption. Consequently, its efficacy and safety are similar with or without concomitant intake of proton-pump inhibitors (PPIs). A simplified DE tablet formulation was developed and tested in two studies. One investigated bioequivalence (BE) of the novel DE tablet versus the commercial DE capsule. The other investigated DE bioavailability (BA) under pretreatment with the PPI rabeprazole and assessed the effect of elevated pH on exposure to dabigatran. METHODS: BE of the novel DE tablet versus the DE capsule was assessed in a randomized two-treatment, four-period, two-sequence crossover study (NCT03070171). The effect of rabeprazole on the BA of the DE tablet was assessed in an open-label, single-arm study (NCT03143166). Both studies were conducted at sites in Japan. Participants were healthy male volunteers, aged ≥ 20-40 years. In the BE study, participants received the DE tablet or capsule (single oral dose, 110 mg); primary endpoints were area under the concentration-time curve from baseline to the last quantifiable data point (AUC0-tz) and maximum plasma concentration (Cmax) of unconjugated dabigatran. In the relative BA study, participants received the DE tablet (single oral dose, 110 mg) with or without rabeprazole pretreatment (once daily for 5 days, 20 mg); primary endpoints were AUC0-tz and Cmax of total dabigatran. RESULTS: In total, 160 participants were randomized in the BE study; 36 participants were enrolled in the BA study. The 90% confidence intervals of geometric mean (gMean) ratios for AUC0-tz (101.4-116.0%) and Cmax (101.8-116.6%) of unconjugated dabigatran were within pre-defined acceptance criteria for BE. In the relative BA study, the gMeans of AUC0-tz (667 to 192 ng h/mL) and Cmax (83.1 to 21.8 ng/mL) were decreased by approximately 70% when the tablet was administered under rabeprazole pretreatment. The reduction in BA was observed at a mean gastric pH of 5.3. Treatment was well tolerated; no deaths, serious adverse events (AEs) or significant AEs were reported in either study. CONCLUSION: The DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE. Registration: ClinicalTrials.gov identifier numbers: NCT03070171, and NCT03143166.

Pharmacokinetic evaluation of differential drug release formulations of rabeprazole in dogs.

Objectives: To develop novel dual release prototype capsule formulations of rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex®) in Beagle dogs. Methods: The dual release prototype formulations of rabeprazole were developed by preparing optimized mini-tablets core which was subsequently coated with barrier/enteric coating using standard excipients. Both novel prototype formulations were subjected for in vitro release and assay by HPLC-UV to assess long term stability. Single dose pharmacokinetic study used a single sequence three treatments crossover design. In Periods 1 and 2, four dogs received oral 20 mg dose of two prototype formulations. In Period 3, all dogs received a 20 mg oral dose of Aciphex® reference product. There was a 1-week washout time between two successive periods. A quantitative analysis of rabeprazole/sulfide metabolite in plasma samples was performed using a validated LC-MS/MS assay and PK parameters were estimated by non-compartmental analysis. Results: The stability of the prototype formulations was confirmed over a period of 24 months with an acceptable assay and dissolution data. One of the novel prototype formulations showed 70% oral bioavailability relative to the reference product. Despite a 30% reduced bioavailability, this showed 1 h delay in peak concentration, longer plasma residence time of rabeprazole (up to 12 h) and longer apparent elimination half-life. Conclusions: The use of a canine model has enabled the selection of a novel dual-release prototype formulation of rabeprazole for further clinical development.

Stereoselective pharmacokinetics of (R)-(+)- and (S)-(-)-rabeprazole in human using chiral LC-MS/MS after administration of rabeprazole sodium enteric-coated tablet.

Rabeprazole is an effective proton pump inhibitor to treat acid-related diseases. To achieve the simultaneous determination of rabeprazole enantiomers in human plasma, a chiral LC-MS/MS method was developed and validated. Acetonitrile including 0.1% ammonium were used as protein precipitating agent. Analytes were separated within 8 minutes on a Chiralpak IC column (4.6 mm × 150 mm, 5 µm). The mobile phase was 10 mM ammonium acetate including 0.2% acetic acid-acetonitrile (35:65, v/v). An API 4000 mass spectrometer was used as detector for the analysis, and the multiple reactions monitoring transitions of m/z 360.1 â†’ 242.2 and 346.1 â†’ 198.1 were opted for quantifying rabeprazole enantiomers and internal standard. Matrix effects were not apparent for each enantiomer and internal standard (esomeprazole), the calibration curves were linear over the concentration of 0.500 to 400 ng·mL-1 , the intra-run precisions were below 5.4%, the inter-run precisions were below 9.9%, and the accuracy was between -9.2% and 9.3%. There was no chiral inversion observed during sample storage, preparation procedure, and analysis, demonstrating that analytes were stable in this study. This method was applied to the stereoselective pharmacokinetic study of (R)-(+)- and (S)-(-)-rabeprazole after oral administration of 10-mg rabeprazole sodium enteric-coated tablet in healthy Chinese subjects.

Stereoselective and nonstereoselective pharmacokinetics of rabeprazole - an overview.

1. Proton pump inhibitors have been extensively used for the treatment of ailments due to increased gastric acid secretion such as peptic ulcers, gastroesophageal reflux disease, etc. 2. There are several approved drugs in the proton pump inhibitor class with the latest entries representing single enantiomer drugs of the previously approved racemic drugs. 3. Despite having a high degree of structural resemblance, rabeprazole, was shown to possess some unique differentiation from other drugs in the class. One of the key distinguishing features of rabeprazole was related to the lesser involvement of polymorphic metabolism in its pharmacokinetic disposition. 4. The review was aimed to provide pharmacokinetic data of rabeprazole from several clinical studies including drug-drug interaction studies where rabeprazole was either a perpetrator drug or victim drug. 5. Additional perspectives on therapy considerations due to the unique metabolic disposition of rabeprazole including the possible issues related to chirality were provided.

Optimized high-dose amoxicillin-proton-pump inhibitor dual therapies fail to achieve high cure rates in China.

Background\Aim: Quadruple daily administration of proton-pump inhibitor (PPI) therapy achieves potent acid inhibition, and combined with amoxicillin, with its pharmacodynamic and pharmacokinetic characteristics, may be efficient for Helicobacter pylori eradication. We compared the efficacy of two optimized high-dose dual therapies with a bismuth-containing quadruple regimen for treating H. pylori infection. Rabeprazole dosages for H. pylori eradication were also evaluated. PATIENTS AND METHODS: Treatment-naive and H. pylori-positive subjects were recruited and randomly apportioned to three treatment groups: Group A (n = 87), rabeprazole 10 mg plus amoxicillin 750 mg (4 times/day for 14 days); Group B (n = 87), rabeprazole 20 mg plus amoxicillin 750 mg (4 times/day for 14 days); and Group C (n = 89), bismuth-containing quadruple regimen consisting of rabeprazole 20 mg, bismuth 220 mg, amoxicillin 1000 mg, and clarithromycin 500 mg (2 times/day for 14 days). Four weeks after treatment discontinuation, patients were examined for H. pylori infection by 13C-urea breath test. The rates of adverse effects, compliance, and eradication were evaluated. RESULTS: Eradication rates in groups A, B, and C were 78.1, 81.6, and 84.3%, respectively, based on intention-to-treat analysis, or 79.1, 83.5, and 86.2%, according to per-protocol analysis. Rates of adverse events and compliance of the three groups were similar. CONCLUSION: For treating H. pylori infection, optimized high-dose amoxicillin-PPI dual therapies failed to achieve high cure rates in China and held no advantage over a bismuth-containing quadruple regimen.

Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption.

PURPOSE: Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria. METHODS: In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. RESULTS: Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

Different effects of lansoprazole and rabeprazole on the plasma voriconazole trough levels in allogeneic hematopoietic cell transplant recipients.

Voriconazole (VRC) is widely used as prophylaxis and in the treatment of invasive fungal disease (IFD) after allogeneic hematopoietic cell transplantation (HCT). We retrospectively examined the results of VRC therapeutic drug monitoring (TDM) in allogeneic HCT recipients. A total of 474 samples were obtained from 59 adult patients who received VRC during the first 100 days following HCT between 2009 and 2014 in our institute. Seventeen patients received VRC for prophylaxis of IFD, and 42 received VRC for the empirical or preemptive therapy for IFD. A total of 299 samples (63 %) were obtained during the administration of the intravenous form of VRC. The median VRC daily dose based on the actual body weight was 6.68 mg/kg/day (range, 1.92-10.41 mg/kg/day). The median VRC trough level was 0.99 mg/l (range, <0.09-5.45 mg/l). The multivariate analysis using a logistic regression model demonstrated significantly higher VRC trough levels (≥1.0 mg/l) in males (P < 0.001), empirical or preemptive therapy (P = 0.002), VRC daily dose based on the actual body weight ≥7 mg/kg/day (P < 0.001), and concomitant use of lansoprazole as compared to rabeprazole (P < 0.001). The concomitant use of calcineurin inhibitors and corticosteroids had no effects on VRC trough levels in multivariate analysis. These data suggest that lansoprazole and rabeprazole have different effects on the plasma VRC trough levels in the allogeneic HCT recipients.

Stomach specific polymeric low density microballoons as a vector for extended delivery of rabeprazole and amoxicillin for treatment of peptic ulcer.

The study was intended to develop a new intra-gastric floating in situ microballoons system for controlled delivery of rabeprazole sodium and amoxicillin trihydrate for the treatment of peptic ulcer disease. Eudragit S-100 and hydroxypropyl methyl cellulose based low density microballoons systems were fabricated by employing varying concentrations of Eudragit S-100 and hydroxypropyl methyl cellulose, to which varying concentrations of drug was added, and formulated by stirring at various speed and time to optimize the process and formulation variable. The formulation variables like concentration and ratio of polymers significantly affected the in vitro drug release from the prepared floating device. The validation of the gastro-retentive potential of the prepared microballoons was carried out in rabbits by orally administration of microballoons formulation containing radio opaque material. The developed formulations showed improved buoyancy and lower ulcer index as compared to that seen with plain drugs. Ulcer protective efficacies were confirmed in ulcer-bearing mouse model. In conclusion, greater compatibility, higher gastro-retention and higher anti-ulcer activity of the presently fabricated formulations to improve potential of formulation for redefining ulcer treatment are presented here. These learning exposed a targeted and sustained drug delivery potential of prepared microballoons in gastric region for ulcer therapeutic intervention as corroborated by in vitro and in vivo findings and, thus, deserves further attention for improved ulcer treatment.

Pharmacokinetics and bioavailability in healthy Chinese volunteers of a novel rabeprazole sterile powder formulation for injection.

Rabeprazole sterile powder for injection (RSPI) is a new formulation, compared with rabeprazole enteric coated tablets. The aim of this study was to evaluate the pharmacokinetic properties and bioavailability of RSPI in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 10, 20, 40 mg, and a multiple doses of 20 mg. A bioavailability study was evaluated following a single dose of 20 mg between RSPI and Pariet® Pharmacokinetic parameters of rabeprazole given in each treatment period were calculated using non-compartmental analysis. In the PK study, after a single intravenous dose of 10, 20, and 40 mg, the main pharmacokinetic parameters for rabeprazole were as follows: Cmax 566.88, 897.23, 2,171.6 ng/mL; AUClast/794.31, 1,122.76, 2,446.85 ng×h/mL, respectively. After multiple doses of 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 991.90 ng/mL, AUClast 1,261.08 ng×h/mL. In the BA study, after a single oral dose of Pariet® 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 582.74 ng/mL, AUClast 1,135.5 ng×h/mL. RSPI produced a less-than-proportional increase in exposure with increasing dose in healthy subjects. The accumulation ratio was 1.0, suggesting RSPI displayed no accumulation after repeated administration. The bioavailability of RSPI was increased by ~ 11% as measured by AUClast compared with Pariet® after a single oral administration.

Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers.

This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.

In vitro and in vivo evaluation of drug-drug interaction between dabigatran and proton pump inhibitors.

To quantify the drug-drug interactions between dabigatran etexilate (DE) and proton pump inhibitors (PPI) and in particular the role of P-gp activity modulation. In the first part of the study, efflux ratios of DE were evaluated using the caco-2 cell line in the presence of pantoprazole, omeprazole, rabeprazole, lansoprazole and ciclosporin A (positive control). The two PPI that reduced the efflux ratio of dabigatran to the greatest and least extent, respectively, were used during the second part of the study, comprising a single-centre, randomised, open-label study with an incomplete Latin square design. Nine healthy volunteers received DE (150 mg) alone, DE (150 mg) with the first PPI and DE (150 mg) with the second PPI in randomised sequence. Dabigatran plasma concentration and thrombin time were measured in blood samples withdrawn at 11 time points after each treatment. Models were built using a nonlinear mixed-effect modelling approach. Omeprazole and rabeprazole were the two PPI that reduced the efflux ratio of DE least and most, respectively. The PK model was based on an inverse Gaussian absorption process with one compartment. The relationship between dabigatran concentration and thrombin time was considered linear. Some PK profiles had dramatically low concentration values due to poor absorption. These profiles were clustered using a between subject model mixture with interoccasion variability. The concomitant administration of PPI did not significantly change dabigatran pharmacokinetics. DE is subject to high absorption variability, precluding evaluation of the effect of PPI on its pharmacokinetics.

Application of a liquid chromatographic/tandem mass spectrometric method to a urinary excretion study of rabeprazole and two of its metabolites in healthy human urine.

To study urinary excretion properties of rabeprazole and two of its metabolites, i.e. rabeprazole thioether and desmethyl rabeprazole thioether in human urine, a sensitive, selective, accurate and precise method for the quantification of rabeprazole and two of its metabolites using a liquid chromatographic/tandem mass spectrometric method has been developed and validated. Starting with a 200 µL urine aliquot, a general sample preparation was performed using protein precipitation with methanol. Analytes were separated on a Dikma Inspire™ C18 column (150 mm × 2.1mm, 5 µm) using a mixture of methanol and aqueous 10mM ammonium acetate buffer containing 0.05% formic acid (55:45, v/v) as mobile phase. Linearity was obtained over the concentration range of 0.1446-96.38 ng/mL, 0.3198-319.8 ng/mL and 0.05160-82.53 ng/mL for rabeprazole, rabeprazole thioether, desmethyl rabeprazole thioether in human urine, respectively. The fully validated method was applied to a urine excretion study of rabeprazole sodium administered as a 30 min intravenous infusion for the first time. The calculated cumulative urinary recovery just reached 0.04745‰, 1.272‰ and 0.1631‰ of dose within 24h post-dose for rabeprazole, rabeprazole thioether, and desmethyl rabeprazole thioether, respectively, after intravenous infusion administration, indicating that rabeprazole and its two main metabolites undergo substantial non-renal elimination in healthy Chinese volunteers.

Helicobacter pylori treatment in children: defining a dose for rabeprazole as a part of a triple therapy regimen.

The proton pump inhibitor, rabeprazole, has been studied in children for the treatment of gastroesophageal reflux disease (GERD). In adults, rabeprazole is indicated for Helicobacter pylori eradication in combination with amoxicillin and clarithromycin. Nonlinear mixed effects modeling was conducted to estimate pharmacokinetic (PK) parameters for rabeprazole and its thioether metabolite from 336 subjects, 35% of whom were children 1-11 years with GERD from phase I and III studies. A 2-compartment disposition model with a transit absorption model provided the best fit for rabeprazole PK. The steady-state area under the concentration-time curves given several candidate doses were simulated to identify a dose per each body weight group that is comparable to a 20 mg twice-daily dose in adults, which is the recommended dose for treatment of H. pylori in adults. Simulations provided the following recommended twice-daily weight-based doses for children ≥1 year and <16 years: 10 mg for 6-10 kg, 15 mg for 10-30 kg, and 20 mg for ≥30 kg.