The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
David A Peura - One of the best experts on this subject based on the ideXlab platform.
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the 12 month safety profile of dexlansoprazole a proton pump inhibitor with a dual Delayed Release Formulation in patients with gastro oesophageal reflux disease
Alimentary Pharmacology & Therapeutics, 2011Co-Authors: Aruna Dabholkar, M M Paris, Maria Claudia Perez, Stuart Atkinson, David A PeuraAbstract:Aliment Pharmacol Ther 2011; 33: 366–377 Summary Background Dexlansoprazole MR is a Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to extend the duration of acid suppression. Aim To assess the 12-month safety of dexlansoprazole MR in patients with symptomatic gastro-oesophageal reflux disease (GERD). Methods In this randomised open-label study, patients received dexlansoprazole MR 60 or 90 mg once-daily for 12 months. Safety was evaluated at months 1, 3, 6, 9 and 12/final visit through physical examinations, laboratory evaluations, endoscopies, gastric biopsies, fasting serum gastrin values and adverse events (AEs). Results Of 591 patients receiving dexlansoprazole MR 60 and 90 mg, 71% and 65%, respectively, experienced ≥1 treatment-emergent AE; the most frequent AE was upper respiratory infection (14% and 13% in the 60- and 90-mg groups). Thirty patients experienced ≥1 serious AE; a majority of serious AEs were unrelated to study drug. No clinically meaningful change in any clinical laboratory parameters was noted. As expected, serum gastrin values rose with dexlansoprazole therapy; increases were not dose related. No clinically concerning trends were identified in gastric pathology results; no endocrine cell hyperplasia, adenocarcinoma, or lymphoma were observed. Conclusions Twelve-month treatment with dexlansoprazole MR 60 and 90 mg was well tolerated by GERD patients in this study (Clinicaltrials.gov identifier NCT00255190).
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The 12‐month safety profile of dexlansoprazole, a proton pump inhibitor with a dual Delayed Release Formulation, in patients with gastro‐oesophageal reflux disease
Alimentary Pharmacology & Therapeutics, 2010Co-Authors: Aruna Dabholkar, M M Paris, Maria Claudia Perez, Stuart Atkinson, David A PeuraAbstract:Aliment Pharmacol Ther 2011; 33: 366–377 Summary Background Dexlansoprazole MR is a Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to extend the duration of acid suppression. Aim To assess the 12-month safety of dexlansoprazole MR in patients with symptomatic gastro-oesophageal reflux disease (GERD). Methods In this randomised open-label study, patients received dexlansoprazole MR 60 or 90 mg once-daily for 12 months. Safety was evaluated at months 1, 3, 6, 9 and 12/final visit through physical examinations, laboratory evaluations, endoscopies, gastric biopsies, fasting serum gastrin values and adverse events (AEs). Results Of 591 patients receiving dexlansoprazole MR 60 and 90 mg, 71% and 65%, respectively, experienced ≥1 treatment-emergent AE; the most frequent AE was upper respiratory infection (14% and 13% in the 60- and 90-mg groups). Thirty patients experienced ≥1 serious AE; a majority of serious AEs were unrelated to study drug. No clinically meaningful change in any clinical laboratory parameters was noted. As expected, serum gastrin values rose with dexlansoprazole therapy; increases were not dose related. No clinically concerning trends were identified in gastric pathology results; no endocrine cell hyperplasia, adenocarcinoma, or lymphoma were observed. Conclusions Twelve-month treatment with dexlansoprazole MR 60 and 90 mg was well tolerated by GERD patients in this study (Clinicaltrials.gov identifier NCT00255190).
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safety profile of dexlansoprazole mr a proton pump inhibitor with a novel dual Delayed Release Formulation global clinical trial experience
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: David A Peura, David C Metz, Aruna Dabholkar, M M Paris, P Yu, S N AtkinsonAbstract:Summary Background Dexlansoprazole MR is a dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole. Aim To assess safety of dexlansoprazole MR in phase 3 clinical trials. Methods Data from 4270 patients receiving dexlansoprazole MR 30 mg (n = 455), 60 mg (n = 2311) or 90 mg (n = 1864); lansoprazole 30 mg (n = 1363); or placebo (n = 896) in six randomized controlled trials and a 12-month safety study were pooled. Safety was assessed via adverse events, vital signs, electrocardiograms, clinical laboratory results and gastric biopsies. Adverse events were summarized per 100 patient-months of exposure to account for imbalances in study drug exposure. Results The number of patients with ≥1 treatment-emergent adverse event per 100 patient-months was higher in placebo (24.49) and lansoprazole (21.06) groups than in any dexlansoprazole MR (15.64–18.75) group. Fewer patients receiving dexlansoprazole MR discontinued therapy because of an adverse event (P ≤ 0.05 vs. placebo). Seven patients died of events considered unrelated to study drug. Mean serum gastrin rose in all groups except placebo; increases were not dose-related. No clinically concerning trends were seen in gastric biopsy results. Endocrine cell hyperplasia, dysplasia and neoplasia were not observed. Conclusion Dexlansoprazole MR 30–90 mg has a safety profile comparable to that of lansoprazole.
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clinical trials healing of erosive oesophagitis with dexlansoprazole mr a proton pump inhibitor with a novel dual Delayed Release Formulation results from two randomized controlled studies
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: Prateek Sharma, Maria Claudia Perez, Stuart Atkinson, Nicholas J Shaheen, B L Pilmer, David A PeuraAbstract:Summary Background Dexlansoprazole MR employs a dual Delayed-Release delivery system that extends drug exposure and prolongs pH control compared with lansoprazole. Aim To assess the efficacy and safety of dexlansoprazole MR in healing erosive oesophagitis (EO). Methods Patients in two identical double-blind, randomized controlled trials (n = 4092) received dexlansoprazole MR 60 or 90 mg or lansoprazole 30 mg once daily. Week 8 healing was assessed using a closed testing procedure – first for non-inferiority, then superiority, vs. lansoprazole. Secondary endpoints included week 4 healing and week 8 healing in patients with moderate-to-severe disease (Los Angeles Classification grades C and D). Life-table and crude rate analyses were performed. Symptoms and tolerability were assessed. Results Dexlansoprazole MR achieved non-inferiority to lansoprazole, allowing testing for superiority. Using life-table analysis, dexlansoprazole MR healed 92–95% of patients in individual studies vs. 86–92% for lansoprazole; the differences were not statistically significant (P > 0.025). Using crude rate analysis, dexlansoprazole MR 90 mg was superior to lansoprazole in both studies and 60 mg was superior in one study. Week 4 healing was >64% with all treatments in both studies. In an integrated analysis of 8-week healing in patients with moderate-to-severe EO, dexlansoprazole MR 90 mg was superior to lansoprazole. All treatments effectively relieved symptoms and were well tolerated. Conclusion Dexlansoprazole MR is highly effective in healing EO and offers benefits over lansoprazole, particularly in moderate-to-severe disease.
Stuart Atkinson - One of the best experts on this subject based on the ideXlab platform.
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Copyright Informa UK Limited 2009 Not for Sale or Comercial Distribution
2020Co-Authors: Majid Vakily, Stuart Atkinson, Jingtao Wu, Weijiang Zhang, Darcy MulfordAbstract:Background: Dexlansoprazole MR is a novel Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing. Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR. Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n ¼40), subjects received dexlansoprazole MR 60, 90, and 120mg and lansoprazole 30mg QD. In study 2 (n ¼45), subjects received dexlansoprazole MR 30 and 60mg and lansoprazole 15mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure. Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma concentration–time profile following administration of dexlansoprazole MR was characterized by two distinct peaks and a prolonged drug exposure during the 24-h dosing interval. Approximate dose proportionality was observed for mean peak plasma concentration and area under the plasma–concentration
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the 12 month safety profile of dexlansoprazole a proton pump inhibitor with a dual Delayed Release Formulation in patients with gastro oesophageal reflux disease
Alimentary Pharmacology & Therapeutics, 2011Co-Authors: Aruna Dabholkar, M M Paris, Maria Claudia Perez, Stuart Atkinson, David A PeuraAbstract:Aliment Pharmacol Ther 2011; 33: 366–377 Summary Background Dexlansoprazole MR is a Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to extend the duration of acid suppression. Aim To assess the 12-month safety of dexlansoprazole MR in patients with symptomatic gastro-oesophageal reflux disease (GERD). Methods In this randomised open-label study, patients received dexlansoprazole MR 60 or 90 mg once-daily for 12 months. Safety was evaluated at months 1, 3, 6, 9 and 12/final visit through physical examinations, laboratory evaluations, endoscopies, gastric biopsies, fasting serum gastrin values and adverse events (AEs). Results Of 591 patients receiving dexlansoprazole MR 60 and 90 mg, 71% and 65%, respectively, experienced ≥1 treatment-emergent AE; the most frequent AE was upper respiratory infection (14% and 13% in the 60- and 90-mg groups). Thirty patients experienced ≥1 serious AE; a majority of serious AEs were unrelated to study drug. No clinically meaningful change in any clinical laboratory parameters was noted. As expected, serum gastrin values rose with dexlansoprazole therapy; increases were not dose related. No clinically concerning trends were identified in gastric pathology results; no endocrine cell hyperplasia, adenocarcinoma, or lymphoma were observed. Conclusions Twelve-month treatment with dexlansoprazole MR 60 and 90 mg was well tolerated by GERD patients in this study (Clinicaltrials.gov identifier NCT00255190).
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The 12‐month safety profile of dexlansoprazole, a proton pump inhibitor with a dual Delayed Release Formulation, in patients with gastro‐oesophageal reflux disease
Alimentary Pharmacology & Therapeutics, 2010Co-Authors: Aruna Dabholkar, M M Paris, Maria Claudia Perez, Stuart Atkinson, David A PeuraAbstract:Aliment Pharmacol Ther 2011; 33: 366–377 Summary Background Dexlansoprazole MR is a Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to extend the duration of acid suppression. Aim To assess the 12-month safety of dexlansoprazole MR in patients with symptomatic gastro-oesophageal reflux disease (GERD). Methods In this randomised open-label study, patients received dexlansoprazole MR 60 or 90 mg once-daily for 12 months. Safety was evaluated at months 1, 3, 6, 9 and 12/final visit through physical examinations, laboratory evaluations, endoscopies, gastric biopsies, fasting serum gastrin values and adverse events (AEs). Results Of 591 patients receiving dexlansoprazole MR 60 and 90 mg, 71% and 65%, respectively, experienced ≥1 treatment-emergent AE; the most frequent AE was upper respiratory infection (14% and 13% in the 60- and 90-mg groups). Thirty patients experienced ≥1 serious AE; a majority of serious AEs were unrelated to study drug. No clinically meaningful change in any clinical laboratory parameters was noted. As expected, serum gastrin values rose with dexlansoprazole therapy; increases were not dose related. No clinically concerning trends were identified in gastric pathology results; no endocrine cell hyperplasia, adenocarcinoma, or lymphoma were observed. Conclusions Twelve-month treatment with dexlansoprazole MR 60 and 90 mg was well tolerated by GERD patients in this study (Clinicaltrials.gov identifier NCT00255190).
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effects of dexlansoprazole mr a novel dual Delayed Release Formulation of a proton pump inhibitor on plasma gastrin levels in healthy subjects
The Journal of Clinical Pharmacology, 2009Co-Authors: Weijiang Zhang, Jingtao Wu, Stuart AtkinsonAbstract:Dexlansoprazole MR is a modified Release Formulation of a proton pump inhibitor being developed for the treatment of acid-related disorders. The purpose of this study is to characterize the plasma gastrin (PG) profile associated with administration of dexlansoprazole MR. Forty-two healthy subjects receive dexlansoprazole MR 90 mg, dexlansoprazole MR 120 mg, and lansoprazole 30 mg once daily for 5 days in a randomized, open-label, 3-period crossover study with at least 14-day washout intervals. Twenty-four-hour PG profiles are obtained at baseline (day – 1 of period 1) and on days 1 and 5 in each period. Fasting PG levels are determined on days 8 and 12 in periods 1 and 2. On day 1, 24-hour PG levels increase from baseline to a similar extent with all regimens. On day 5, 24-hour PG levels with both dexlansoprazole MR regimens increase further and to a similar extent and are slightly higher than PG levels with lansoprazole. For all regimens, fasting PG levels on days 5 and 6 are higher than baseline levels (P < .05) and start to decrease by day 8, returning to near baseline at day 12. In this study, dexlansoprazole MR administration results in moderate increases in PG, similar to lansoprazole, which return to baseline levels within 7 days post dosing.
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clinical trials healing of erosive oesophagitis with dexlansoprazole mr a proton pump inhibitor with a novel dual Delayed Release Formulation results from two randomized controlled studies
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: Prateek Sharma, Maria Claudia Perez, Stuart Atkinson, Nicholas J Shaheen, B L Pilmer, David A PeuraAbstract:Summary Background Dexlansoprazole MR employs a dual Delayed-Release delivery system that extends drug exposure and prolongs pH control compared with lansoprazole. Aim To assess the efficacy and safety of dexlansoprazole MR in healing erosive oesophagitis (EO). Methods Patients in two identical double-blind, randomized controlled trials (n = 4092) received dexlansoprazole MR 60 or 90 mg or lansoprazole 30 mg once daily. Week 8 healing was assessed using a closed testing procedure – first for non-inferiority, then superiority, vs. lansoprazole. Secondary endpoints included week 4 healing and week 8 healing in patients with moderate-to-severe disease (Los Angeles Classification grades C and D). Life-table and crude rate analyses were performed. Symptoms and tolerability were assessed. Results Dexlansoprazole MR achieved non-inferiority to lansoprazole, allowing testing for superiority. Using life-table analysis, dexlansoprazole MR healed 92–95% of patients in individual studies vs. 86–92% for lansoprazole; the differences were not statistically significant (P > 0.025). Using crude rate analysis, dexlansoprazole MR 90 mg was superior to lansoprazole in both studies and 60 mg was superior in one study. Week 4 healing was >64% with all treatments in both studies. In an integrated analysis of 8-week healing in patients with moderate-to-severe EO, dexlansoprazole MR 90 mg was superior to lansoprazole. All treatments effectively relieved symptoms and were well tolerated. Conclusion Dexlansoprazole MR is highly effective in healing EO and offers benefits over lansoprazole, particularly in moderate-to-severe disease.
Darcy Mulford - One of the best experts on this subject based on the ideXlab platform.
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Copyright Informa UK Limited 2009 Not for Sale or Comercial Distribution
2020Co-Authors: Majid Vakily, Stuart Atkinson, Jingtao Wu, Weijiang Zhang, Darcy MulfordAbstract:Background: Dexlansoprazole MR is a novel Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing. Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR. Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n ¼40), subjects received dexlansoprazole MR 60, 90, and 120mg and lansoprazole 30mg QD. In study 2 (n ¼45), subjects received dexlansoprazole MR 30 and 60mg and lansoprazole 15mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure. Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma concentration–time profile following administration of dexlansoprazole MR was characterized by two distinct peaks and a prolonged drug exposure during the 24-h dosing interval. Approximate dose proportionality was observed for mean peak plasma concentration and area under the plasma–concentration
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Development of Dexlansoprazole Delayed-Release Capsules, a Dual Delayed-Release Proton Pump Inhibitor
Journal of Pharmaceutical Sciences, 2019Co-Authors: Haiyan Grady, Yusuke Murakawa, Darcy Mulford, Michael KukulkaAbstract:Abstract Proton pump inhibitors (PPIs) are widely used for treating acid-related disorders. For an “ideal PPI,” achieving maximal absorption and sustaining pharmacodynamic effects through the 24-h dosing cycle are critical features. Dexlansoprazole offers a relevant case study on how an improved PPI was developed capitalizing on the rational optimization of a precursor molecule—in this case, using lansoprazole as a starting point, leveraging its chemical properties on pharmacokinetics, and exploring optimized Formulations. Dexlansoprazole is the R(+)-enantiomer of lansoprazole and shows stereoselective differences in absorption and metabolism compared with the racemic mixture of lansoprazole. The Formulation was further refined to use pulsate-type granules with enteric coating to withstand acidic gastric conditions, while allowing prolonged absorption in the proximal and distal small intestine. As a result, the dual Delayed-Release Formulation of dexlansoprazole has a plasma concentration-time profile characterized by 2 distinct peaks, leading to an extended duration of therapeutic plasma drug concentrations compared with the conventional Delayed-Release lansoprazole Formulation. The dual Delayed-Release Formulation maintains plasma drug concentrations longer than the lansoprazole Delayed-Release Formulation at all doses.
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review article dual Delayed Release Formulation of dexlansoprazole mr a novel approach to overcome the limitations of conventional single Release proton pump inhibitor therapy
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: David C Metz, Majid Vakily, T Dixit, Darcy MulfordAbstract:Summary Background Proton pump inhibitors (PPIs) provide the most effective pharmacotherapy for treating acid-related disorders. However, PPIs do not completely control acid over 24 h with once-daily dosing. Aims To discuss limitations inherent in the pharmacokinetics (PK) and pharmacodynamics of conventional PPI Formulations, which provide a single drug Release. Also, to consider approaches to extending the duration of acid suppression focusing on dexlansoprazole MR, a PPI with a novel Dual Delayed Release (DDR) Formulation. Method We reviewed the available literature regarding marketed and investigational PPIs. Results Non-standard dosing of currently marketed PPIs has produced incremental advances in acid control. Multiple approaches are being evaluated to enhance acid suppression with PPIs. Dexlansoprazole MR is a DDR Formulation of dexlansoprazole, an enantiomer of lansoprazole, with two distinct drug Release periods to prolong the plasma dexlansoprazole concentration–time profile and extend duration of acid suppression. Clinical studies show that dexlansoprazole MR produces a dual-peak PK profile that maintains therapeutic plasma drug concentrations longer than lansoprazole, with a single-peak PK profile, and increases the percentage of time that intragastric pH >4. Conclusions Novel drug delivery platforms, including the dexlansoprazole MR DDR Formulation, may improve acid suppression and offer benefits over conventional single Release PPI Formulations.
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Pharmacokinetics and Pharmacodynamics of a Known Active PPI With a Novel Dual Delayed Release Technology, Dexlansoprazole MR: A Combined Analysis of Randomized Controlled Clinical Trials
Current Medical Research and Opinion, 2009Co-Authors: Majid Vakily, Stuart Atkinson, Jingtao Wu, Weijiang Zhang, Darcy MulfordAbstract:ABSTRACTBackground: Dexlansoprazole MR is a novel Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing.Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR.Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n = 40), subjects received dexlansoprazole MR 60, 90, and 120 mg and lansoprazole 30 mg QD. In study 2 (n = 45), subjects received dexlansoprazole MR 30 and 60 mg and lansoprazole 15 mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure.Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma c...
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Drug Interaction Studies with Dexlansoprazole Modified Release (TAK-390MR), a Proton Pump Inhibitor with a Dual Delayed-Release Formulation
Clinical Drug Investigation, 2009Co-Authors: Majid Vakily, Jingtao Wu, Lhanoo Gunawardhana, Darcy MulfordAbstract:Background and objective: Most proton pump inhibitors are extensively metabolized by cytochrome P450 (CYP) isoenzymes, as are many other drugs, giving rise to potential drug-drug interactions. Dexlansoprazole modified Release (MR) [TAK-390MR] is a modified-Release Formulation of dexlansoprazole (TAK-390), an enantiomer of lansoprazole, which employs an innovative Dual Delayed Release™ technology designed to prolong the plasma dexlansoprazole concentration-time profile following once-daily oral administration. As with lansoprazole, dexlansoprazole is metabolized mainly by CYP3A and CYP2C19. Based on in vitro studies, dexlansoprazole has the potential to inhibit activity of these isoenzymes and also may induce human hepatic CYP1A and CYP2C9 activity. To determine whether dexlansoprazole has an effect on these isoenzymes in vivo , drug interaction studies with dexlansoprazole MR were conducted. Methods: Four separate randomized, double-blind, two-way crossover, placebo-controlled, single-centre studies were conducted in healthy volunteers to evaluate the effect of dexlansoprazole on the pharmacokinetics of four test substrates (diazepam, phenytoin, theophylline [administered as intravenous aminophylline] and warfarin), which were selected based on in vitro and/or in vivo data that suggest a potential drug interaction with CYP isoenzymes or potentially coadministered narrow therapeutic index drugs. In each study, dexlansoprazole MR 90 mg or placebo was administered once daily for 9 or 11 days in each period. Subjects received a single dose of test substrate in each study period. Pharmacokinetic parameters of the test substrates were estimated using noncompartmental methods. A conclusion of no effect of dexlansoprazole MR on the test substrate was made if the 90% confidence intervals (CIs) for the ratios of the central values for the observed maximum plasma drug concentration (C_max) and the area under the plasma concentration-time curve (AUC) of test substrate administered with dexlansoprazole MR versus placebo were within 0.80–1.25 based on an analysis of variance model. The potential for a pharmacodynamic interaction was also assessed for warfarin using prothrombin time, measured as the international normalized ratio. Routine safety assessments were conducted in these studies. Results: Mean C_max and AUC values were generally similar for each test substrate when administered with multiple once-daily doses of dexlansoprazole MR or placebo. The 90% CIs for the bioavailability of these test substrates administered with dexlansoprazole MR relative to that obtained when the substrates were administered with placebo were within the bioequivalency range of 0.80–1.25, indicating that multiple doses of dexlansoprazole MR had no effect on the pharmacokinetics of these drugs. Additionally, dexlansoprazole MR had no effect on the pharmacodynamics of warfarin. Administration of these drugs with dexlansoprazole MR 90 mg or placebo was well tolerated; the only serious adverse event, which led to a subject’s discontinuation from the study, was considered unrelated to study drugs. Conclusions: Coadministration of dexlansoprazole MR with diazepam, phenytoin or theophylline did not affect the pharmacokinetics of these drugs, and therefore is unlikely to alter the pharmacokinetic profile of other drugs metabolized by CYP2C19, CYP2C9, CYP1A2 and perhaps CYP3A. Additionally, dexlansoprazole MR coadministered with warfarin did not affect the pharmacokinetics of the warfarin enantiomers and had no effect on the anticoagulant activity of warfarin. Dexlansoprazole MR was well tolerated in these trials of healthy subjects.
Majid Vakily - One of the best experts on this subject based on the ideXlab platform.
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Copyright Informa UK Limited 2009 Not for Sale or Comercial Distribution
2020Co-Authors: Majid Vakily, Stuart Atkinson, Jingtao Wu, Weijiang Zhang, Darcy MulfordAbstract:Background: Dexlansoprazole MR is a novel Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing. Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR. Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n ¼40), subjects received dexlansoprazole MR 60, 90, and 120mg and lansoprazole 30mg QD. In study 2 (n ¼45), subjects received dexlansoprazole MR 30 and 60mg and lansoprazole 15mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure. Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma concentration–time profile following administration of dexlansoprazole MR was characterized by two distinct peaks and a prolonged drug exposure during the 24-h dosing interval. Approximate dose proportionality was observed for mean peak plasma concentration and area under the plasma–concentration
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review article dual Delayed Release Formulation of dexlansoprazole mr a novel approach to overcome the limitations of conventional single Release proton pump inhibitor therapy
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: David C Metz, Majid Vakily, T Dixit, Darcy MulfordAbstract:Summary Background Proton pump inhibitors (PPIs) provide the most effective pharmacotherapy for treating acid-related disorders. However, PPIs do not completely control acid over 24 h with once-daily dosing. Aims To discuss limitations inherent in the pharmacokinetics (PK) and pharmacodynamics of conventional PPI Formulations, which provide a single drug Release. Also, to consider approaches to extending the duration of acid suppression focusing on dexlansoprazole MR, a PPI with a novel Dual Delayed Release (DDR) Formulation. Method We reviewed the available literature regarding marketed and investigational PPIs. Results Non-standard dosing of currently marketed PPIs has produced incremental advances in acid control. Multiple approaches are being evaluated to enhance acid suppression with PPIs. Dexlansoprazole MR is a DDR Formulation of dexlansoprazole, an enantiomer of lansoprazole, with two distinct drug Release periods to prolong the plasma dexlansoprazole concentration–time profile and extend duration of acid suppression. Clinical studies show that dexlansoprazole MR produces a dual-peak PK profile that maintains therapeutic plasma drug concentrations longer than lansoprazole, with a single-peak PK profile, and increases the percentage of time that intragastric pH >4. Conclusions Novel drug delivery platforms, including the dexlansoprazole MR DDR Formulation, may improve acid suppression and offer benefits over conventional single Release PPI Formulations.
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clinical trial the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole mr a novel dual Delayed Release Formulation of a proton pump inhibitor evidence for dosing flexibility
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: Majid Vakily, Jingtao Wu, D Mulford, S N AtkinsonAbstract:Summary Background Dexlansoprazole MR is a proton pump inhibitor with a Dual Delayed Release (DDR) Formulation designed to prolong the dexlansoprazole plasma concentration–time profile. The presence of food or time of dosing relative to food may affect dexlansoprazole absorption. Aims To evaluate the effect of food on the pharmacokinetics (PK) and pharmacodynamics (PD) of dexlansoprazole following oral administration of dexlansoprazole MR. Methods In this open-label, single-dose, randomized, 4-way crossover study, 48 healthy subjects received placebo (day 1) and dexlansoprazole MR 90 mg (day 3) after fasting, 5 or 30 min before a high-fat breakfast, or 30 min after a high-fat breakfast. Intragastric pH (days 1 and 3) and PK (day 3) of dexlansoprazole were assessed over a 24-h interval after each dose. Results Following administration of dexlansoprazole MR under fasted/fed conditions, mean dexlansoprazole plasma concentration–time profiles generally exhibited two distinct peaks, resulting from the DDR Formulation. Increases in dexlansoprazole maximum plasma concentration (12–31%) and area under the plasma concentration–time curve (9–21%) were observed with the fed regimens; however, differences in intragastric pH were not considered clinically relevant. Conclusion Dexlansoprazole MR can be administered without regard to food or the timing of food in most patients.
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Pharmacokinetics and Pharmacodynamics of a Known Active PPI With a Novel Dual Delayed Release Technology, Dexlansoprazole MR: A Combined Analysis of Randomized Controlled Clinical Trials
Current Medical Research and Opinion, 2009Co-Authors: Majid Vakily, Stuart Atkinson, Jingtao Wu, Weijiang Zhang, Darcy MulfordAbstract:ABSTRACTBackground: Dexlansoprazole MR is a novel Dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration–time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing.Objectives: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure–response relationship following oral administration of dexlansoprazole MR.Methods: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n = 40), subjects received dexlansoprazole MR 60, 90, and 120 mg and lansoprazole 30 mg QD. In study 2 (n = 45), subjects received dexlansoprazole MR 30 and 60 mg and lansoprazole 15 mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure.Results: Data from 83 subjects were analyzed. The dexlansoprazole plasma c...
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Drug Interaction Studies with Dexlansoprazole Modified Release (TAK-390MR), a Proton Pump Inhibitor with a Dual Delayed-Release Formulation
Clinical Drug Investigation, 2009Co-Authors: Majid Vakily, Jingtao Wu, Lhanoo Gunawardhana, Darcy MulfordAbstract:Background and objective: Most proton pump inhibitors are extensively metabolized by cytochrome P450 (CYP) isoenzymes, as are many other drugs, giving rise to potential drug-drug interactions. Dexlansoprazole modified Release (MR) [TAK-390MR] is a modified-Release Formulation of dexlansoprazole (TAK-390), an enantiomer of lansoprazole, which employs an innovative Dual Delayed Release™ technology designed to prolong the plasma dexlansoprazole concentration-time profile following once-daily oral administration. As with lansoprazole, dexlansoprazole is metabolized mainly by CYP3A and CYP2C19. Based on in vitro studies, dexlansoprazole has the potential to inhibit activity of these isoenzymes and also may induce human hepatic CYP1A and CYP2C9 activity. To determine whether dexlansoprazole has an effect on these isoenzymes in vivo , drug interaction studies with dexlansoprazole MR were conducted. Methods: Four separate randomized, double-blind, two-way crossover, placebo-controlled, single-centre studies were conducted in healthy volunteers to evaluate the effect of dexlansoprazole on the pharmacokinetics of four test substrates (diazepam, phenytoin, theophylline [administered as intravenous aminophylline] and warfarin), which were selected based on in vitro and/or in vivo data that suggest a potential drug interaction with CYP isoenzymes or potentially coadministered narrow therapeutic index drugs. In each study, dexlansoprazole MR 90 mg or placebo was administered once daily for 9 or 11 days in each period. Subjects received a single dose of test substrate in each study period. Pharmacokinetic parameters of the test substrates were estimated using noncompartmental methods. A conclusion of no effect of dexlansoprazole MR on the test substrate was made if the 90% confidence intervals (CIs) for the ratios of the central values for the observed maximum plasma drug concentration (C_max) and the area under the plasma concentration-time curve (AUC) of test substrate administered with dexlansoprazole MR versus placebo were within 0.80–1.25 based on an analysis of variance model. The potential for a pharmacodynamic interaction was also assessed for warfarin using prothrombin time, measured as the international normalized ratio. Routine safety assessments were conducted in these studies. Results: Mean C_max and AUC values were generally similar for each test substrate when administered with multiple once-daily doses of dexlansoprazole MR or placebo. The 90% CIs for the bioavailability of these test substrates administered with dexlansoprazole MR relative to that obtained when the substrates were administered with placebo were within the bioequivalency range of 0.80–1.25, indicating that multiple doses of dexlansoprazole MR had no effect on the pharmacokinetics of these drugs. Additionally, dexlansoprazole MR had no effect on the pharmacodynamics of warfarin. Administration of these drugs with dexlansoprazole MR 90 mg or placebo was well tolerated; the only serious adverse event, which led to a subject’s discontinuation from the study, was considered unrelated to study drugs. Conclusions: Coadministration of dexlansoprazole MR with diazepam, phenytoin or theophylline did not affect the pharmacokinetics of these drugs, and therefore is unlikely to alter the pharmacokinetic profile of other drugs metabolized by CYP2C19, CYP2C9, CYP1A2 and perhaps CYP3A. Additionally, dexlansoprazole MR coadministered with warfarin did not affect the pharmacokinetics of the warfarin enantiomers and had no effect on the anticoagulant activity of warfarin. Dexlansoprazole MR was well tolerated in these trials of healthy subjects.
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safety profile of dexlansoprazole mr a proton pump inhibitor with a novel dual Delayed Release Formulation global clinical trial experience
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: David A Peura, David C Metz, Aruna Dabholkar, M M Paris, P Yu, S N AtkinsonAbstract:Summary Background Dexlansoprazole MR is a dual Delayed Release Formulation of dexlansoprazole, an enantiomer of lansoprazole. Aim To assess safety of dexlansoprazole MR in phase 3 clinical trials. Methods Data from 4270 patients receiving dexlansoprazole MR 30 mg (n = 455), 60 mg (n = 2311) or 90 mg (n = 1864); lansoprazole 30 mg (n = 1363); or placebo (n = 896) in six randomized controlled trials and a 12-month safety study were pooled. Safety was assessed via adverse events, vital signs, electrocardiograms, clinical laboratory results and gastric biopsies. Adverse events were summarized per 100 patient-months of exposure to account for imbalances in study drug exposure. Results The number of patients with ≥1 treatment-emergent adverse event per 100 patient-months was higher in placebo (24.49) and lansoprazole (21.06) groups than in any dexlansoprazole MR (15.64–18.75) group. Fewer patients receiving dexlansoprazole MR discontinued therapy because of an adverse event (P ≤ 0.05 vs. placebo). Seven patients died of events considered unrelated to study drug. Mean serum gastrin rose in all groups except placebo; increases were not dose-related. No clinically concerning trends were seen in gastric biopsy results. Endocrine cell hyperplasia, dysplasia and neoplasia were not observed. Conclusion Dexlansoprazole MR 30–90 mg has a safety profile comparable to that of lansoprazole.
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clinical trial the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole mr a novel dual Delayed Release Formulation of a proton pump inhibitor evidence for dosing flexibility
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: Majid Vakily, Jingtao Wu, D Mulford, S N AtkinsonAbstract:Summary Background Dexlansoprazole MR is a proton pump inhibitor with a Dual Delayed Release (DDR) Formulation designed to prolong the dexlansoprazole plasma concentration–time profile. The presence of food or time of dosing relative to food may affect dexlansoprazole absorption. Aims To evaluate the effect of food on the pharmacokinetics (PK) and pharmacodynamics (PD) of dexlansoprazole following oral administration of dexlansoprazole MR. Methods In this open-label, single-dose, randomized, 4-way crossover study, 48 healthy subjects received placebo (day 1) and dexlansoprazole MR 90 mg (day 3) after fasting, 5 or 30 min before a high-fat breakfast, or 30 min after a high-fat breakfast. Intragastric pH (days 1 and 3) and PK (day 3) of dexlansoprazole were assessed over a 24-h interval after each dose. Results Following administration of dexlansoprazole MR under fasted/fed conditions, mean dexlansoprazole plasma concentration–time profiles generally exhibited two distinct peaks, resulting from the DDR Formulation. Increases in dexlansoprazole maximum plasma concentration (12–31%) and area under the plasma concentration–time curve (9–21%) were observed with the fed regimens; however, differences in intragastric pH were not considered clinically relevant. Conclusion Dexlansoprazole MR can be administered without regard to food or the timing of food in most patients.