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Maria Claudia Perez - One of the best experts on this subject based on the ideXlab platform.

  • Dexlansoprazole and esomeprazole do not affect bone homeostasis in healthy postmenopausal women
    2019
    Co-Authors: Karen E Hansen, Sai Nudurupati, David C. Metz, Jeri W Nieves, Maria Claudia Perez
    Abstract:

    Background & Aims Epidemiological studies have associated proton pump inhibitor (PPI) therapy with osteoporotic fractures, but it is not clear if PPIs directly cause osteoporosis. We evaluated the effect of Dexlansoprazole and esomeprazole on bone turnover, bone mineral density (BMD), true fractional calcium absorption (TFCA), serum and urine levels of minerals, and levels of parathyroid hormone (PTH) in healthy postmenopausal women. Methods We performed a prospective, multicenter, double-blind study of 115 healthy, postmenopausal women (45 to 75 years of age) from November 4, 2010, through August 7, 2014. Women were randomly assigned to groups given Dexlansoprazole (60 mg), esomeprazole (40 mg), or placebo daily for 26 weeks. We measured plasma levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at 0 (baseline), 13, and 26 weeks. Primary outcomes were percent change in P1NP and CTX between weeks 0 and 26. We also measured changes in serum and urine levels of mineral, BMD, PTH (all subjects), and TFCA (n = 30). Results Between baseline and week 26, there were no significant within-group differences in markers of bone turnover; there was a nonsignificant increase in CTX levels in the Dexlansoprazole group (0.12 ng/mL). The esomeprazole and Dexlansoprazole groups had significantly increased levels of P1NP (18.2% and 19.2%, respectively) and CTX (22.0% and 27.4%, respectively) at week 26 compared with the placebo group, although these values remained within normal ranges. There were no statistically significant differences between groups in serum or urine levels of minerals, BMD, or PTH at week 26. PPI therapy did not reduce TFCA. Conclusions In a prospective study of postmenopausal women, we found significant increases in markers of bone turnover in women given PPI therapy compared with women given placebo, but levels remained within the normal reference range. We found no significant differences among groups in changes in BMD, PTH, serum or urine levels of minerals, or TFCA. Our findings indicate that 26 weeks of treatment with a PPI has no clinically meaningful effects on bone homeostasis. Clinicaltrials.gov no: NCT01216293

  • dual delayed release Dexlansoprazole for healing and maintenance of healed erosive esophagitis a safety study in adolescents
    2019
    Co-Authors: David A Gremse, Benjamin D Gold, Betsy Pilmer, Barbara Hunt, Bartosz Korczowski, Maria Claudia Perez
    Abstract:

    In gastroesophageal reflux disease (GERD), the frequency of heartburn symptoms and erosive esophagitis (EE) increases with age in children and adolescents. Proton pump inhibitor, Dexlansoprazole, is approved for healing EE of all grades, maintenance of healed EE, relief of heartburn, and treatment of symptomatic non-erosive GERD in patients ≥ 12 years. To assess safety and efficacy of Dexlansoprazole dual delayed-release capsule in healing of EE and maintenance of healed EE in adolescents. A multicenter, phase 2, 36-week study was conducted in 62 adolescents (12–17 years) with endoscopically confirmed EE. Patients received Dexlansoprazole 60 mg once daily (QD) during open-label healing phase. Those with confirmed healing at week 8 were randomized to Dexlansoprazole 30 mg QD or placebo during 16-week, double-blind maintenance phase, with subsequent treatment-free follow-up of ≥ 12 weeks. Primary endpoints were treatment-emergent adverse events (TEAEs) in ≥ 5% of patients during treatment. Secondary endpoints included percentages of patients with healing of EE and with maintenance of healed EE. 88% of patients achieved EE healing, and 61.3% reported a TEAE [headache (12.9%), oropharyngeal pain (8.1%), diarrhea (6.5%), and nasopharyngitis (6.5%)]. During maintenance phase, healing was maintained in 82% and 58% of Dexlansoprazole and placebo groups, respectively. 72.0% of Dexlansoprazole-treated patients reported TEAEs, which included headache (24.0%), abdominal pain (12.0%), nasopharyngitis (12.0%), pharyngitis (12.0%), sinusitis (12.0%), bronchitis (8.0%), upper respiratory tract infection (8.0%), and insomnia (8.0%); 61.5% experienced a TEAE with placebo. Dexlansoprazole is safe and efficacious for healing EE and maintenance of healed EE in adolescents.

  • bioavailability of Dexlansoprazole delayed release capsule granules when administered via nasogastric tube or orally via syringe
    2018
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Objective To assess the effect of route of administration on the bioavailability of Dexlansoprazole 60 mg delayed-release capsule granules. Methods One open-label, Phase I, single-dose, 3-period crossover study was conducted in healthy adults. The bioavailability of Dexilant® (Dexlansoprazole) after Dexlansoprazole capsule granules were mixed with water and administered via 16 French nasogastric tube or orally via syringe was compared to administration of the intact capsule in the fasted state, swallowed with water. Blood samples were collected before and after dosing to determine Dexlansoprazole pharmacokinetic parameter estimates and plasma concentrations. Results Similar values for area under the plasma concentration-time curve and observed maximum plasma concentration were achieved when the Dexlansoprazole 60 mg capsule was administered as the intact capsule or when the granules were mixed with water and administered via nasogastric tube or orally via syringe. The primary endpoints of maximum plasma concentration and area under the plasma concentration-time curve demonstrated bioequivalence when assessing these alternative routes of administration. Most adverse events were rated as mild and were comparable irrespective of administration route. Conclusion Systemic exposure to Dexlansoprazole was equivalent regardless of administration route. The Dexlansoprazole capsule was well tolerated.

  • Dexlansoprazole for heartburn relief in adolescents with symptomatic nonerosive gastro esophageal reflux disease
    2017
    Co-Authors: Benjamin D Gold, Maria Claudia Perez, Betsy Pilmer, Barbara Hunt, Jaroslaw Kierkuś, David A Gremse
    Abstract:

    Proton pump inhibitors are commonly used to treat gastro-esophageal reflux disease (GERD) and nonerosive GERD (NERD) in adolescents and adults. Despite the efficacy of available medications, many patients have persisting symptoms, indicating a need for more effective agents. To assess the safety and efficacy of Dexlansoprazole dual delayed-release capsules in adolescents for treatment of symptomatic NERD. A phase 2, open-label, multicenter study was conducted in adolescents aged 12–17 years. After a 21-day screening period, adolescents with endoscopically confirmed NERD received a daily dose of 30-mg Dexlansoprazole for 4 weeks. The primary endpoint was treatment-emergent adverse events (TEAEs) experienced by ≥5% of patients. The secondary endpoint was the percentage of days with neither daytime nor nighttime heartburn. Heartburn symptoms and severity were recorded daily in patient electronic diaries and independently assessed by the investigator, along with patient-reported quality of life, at the beginning and end of the study. Diarrhea and headache were the only TEAEs reported by ≥5% of patients. Dexlansoprazole-treated patients (N = 104) reported a median 47.3% of days with neither daytime nor nighttime heartburn. Symptoms such as epigastric pain, acid regurgitation, and heartburn improved in severity for 73–80% of patients. Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire-Adolescents-Short Form symptom and impact subscale scores (scaled 1–5) each decreased by an average of 0.7 units at week 4. Use of 30-mg Dexlansoprazole in adolescent NERD was generally well tolerated and had beneficial effects on improving heartburn symptoms and quality of life. This study has the ClinicalTrials.gov identifier NCT01642602.

  • bioavailability of a Dexlansoprazole delayed release orally disintegrating tablet effects of food and mode of administration
    2017
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Background Dexlansoprazole is a proton pump inhibitor (PPI) approved for use in dual delayed-release capsule and orally disintegrating tablet (ODT) formulations. Aim To assess effects of food, water, and route of administration on the bioavailability of Dexlansoprazole 30-mg ODT. Methods Two separate open-label, phase 1, single-dose crossover studies were conducted in healthy adults. In study 1, pharmacokinetic parameters were analyzed in participants receiving Dexlansoprazole ODT in a fed or fasted state with and without water. In study 2, the bioavailability of Dexlansoprazole after administration via oral syringe or nasogastric (NG) tube, or after swallowing intact with water was compared to ODT administration in the fasted state, swallowed without water. Blood samples for determining Dexlansoprazole plasma concentrations and pharmacokinetic parameter estimates were collected before and after dosing. Results Equivalent values for area under the plasma concentration-time curve (AUC) were observed in the fed and fasted states, but the maximum observed plasma concentration (Cmax) was 38% lower in the fed state; therefore, bioequivalence was not achieved. A water rinse following standard ODT administration decreased Dexlansoprazole bioavailability, with lower Cmax and AUC values than when ODT was administered without a water rinse. Bioequivalence was demonstrated when comparing the alternative routes of administration, including via oral syringe or NG tube with standard ODT administration. Unlike with a water rinse, bioequivalence to standard ODT administration (i.e., without water) was demonstrated when swallowing the ODT intact with water. Rates of adverse events were comparable irrespective of administration route in the fasted state (6.7%-9.3%) and were 12% higher in the fed state than in the fasted state. Conclusion The AUC from the Dexlansoprazole ODT was equivalent when administered in the fed and fasted states. Equivalent systemic exposure to Dexlansoprazole was achieved regardless of the administration route.

Michael Kukulka - One of the best experts on this subject based on the ideXlab platform.

  • Development of Dexlansoprazole Delayed-Release Capsules, a Dual Delayed-Release Proton Pump Inhibitor
    2019
    Co-Authors: Haiyan Grady, Yusuke Murakawa, Darcy Mulford, Michael Kukulka
    Abstract:

    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.

  • bioavailability of Dexlansoprazole delayed release capsule granules when administered via nasogastric tube or orally via syringe
    2018
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Objective To assess the effect of route of administration on the bioavailability of Dexlansoprazole 60 mg delayed-release capsule granules. Methods One open-label, Phase I, single-dose, 3-period crossover study was conducted in healthy adults. The bioavailability of Dexilant® (Dexlansoprazole) after Dexlansoprazole capsule granules were mixed with water and administered via 16 French nasogastric tube or orally via syringe was compared to administration of the intact capsule in the fasted state, swallowed with water. Blood samples were collected before and after dosing to determine Dexlansoprazole pharmacokinetic parameter estimates and plasma concentrations. Results Similar values for area under the plasma concentration-time curve and observed maximum plasma concentration were achieved when the Dexlansoprazole 60 mg capsule was administered as the intact capsule or when the granules were mixed with water and administered via nasogastric tube or orally via syringe. The primary endpoints of maximum plasma concentration and area under the plasma concentration-time curve demonstrated bioequivalence when assessing these alternative routes of administration. Most adverse events were rated as mild and were comparable irrespective of administration route. Conclusion Systemic exposure to Dexlansoprazole was equivalent regardless of administration route. The Dexlansoprazole capsule was well tolerated.

  • bioavailability of a Dexlansoprazole delayed release orally disintegrating tablet effects of food and mode of administration
    2017
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Background Dexlansoprazole is a proton pump inhibitor (PPI) approved for use in dual delayed-release capsule and orally disintegrating tablet (ODT) formulations. Aim To assess effects of food, water, and route of administration on the bioavailability of Dexlansoprazole 30-mg ODT. Methods Two separate open-label, phase 1, single-dose crossover studies were conducted in healthy adults. In study 1, pharmacokinetic parameters were analyzed in participants receiving Dexlansoprazole ODT in a fed or fasted state with and without water. In study 2, the bioavailability of Dexlansoprazole after administration via oral syringe or nasogastric (NG) tube, or after swallowing intact with water was compared to ODT administration in the fasted state, swallowed without water. Blood samples for determining Dexlansoprazole plasma concentrations and pharmacokinetic parameter estimates were collected before and after dosing. Results Equivalent values for area under the plasma concentration-time curve (AUC) were observed in the fed and fasted states, but the maximum observed plasma concentration (Cmax) was 38% lower in the fed state; therefore, bioequivalence was not achieved. A water rinse following standard ODT administration decreased Dexlansoprazole bioavailability, with lower Cmax and AUC values than when ODT was administered without a water rinse. Bioequivalence was demonstrated when comparing the alternative routes of administration, including via oral syringe or NG tube with standard ODT administration. Unlike with a water rinse, bioequivalence to standard ODT administration (i.e., without water) was demonstrated when swallowing the ODT intact with water. Rates of adverse events were comparable irrespective of administration route in the fasted state (6.7%-9.3%) and were 12% higher in the fed state than in the fasted state. Conclusion The AUC from the Dexlansoprazole ODT was equivalent when administered in the fed and fasted states. Equivalent systemic exposure to Dexlansoprazole was achieved regardless of the administration route.

  • pharmacokinetics and pharmacodynamics of an orally disintegrating tablet formulation of Dexlansoprazole
    2016
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Background:The pharmacokinetics and pharmacodynamics of a novel orally disintegrating tablet (ODT) formulation of delayed-release Dexlansoprazole 30 mg was evaluated versus the Dexlansoprazole 30 mg capsule in this phase I, open-label, multiple-dose, randomized, two-period crossover study.Methods:Healthy adults received daily doses of 30 mg Dexlansoprazole ODT or 30 mg Dexlansoprazole delayed-release capsule for 5 days during two treatment periods, separated by a 7-day washout interval. Blood samples for Dexlansoprazole plasma concentrations and intragastric pH measurements were collected through 24 hours postdose on days 1 and 5 of each period.Results:Bioequivalence between the 30 mg ODT and 30 mg capsule dosage forms was demonstrated by the primary endpoints of Dexlansoprazole peak concentration (Cmax) and systemic exposure (AUC) values contained within the prespecified 90% confidence interval (CI) range of 0.80–1.25. Additional primary endpoints of intragastric mean pH values and percentage of time wit...

  • bioavailability safety and pharmacodynamics of delayed release Dexlansoprazole administered as two 30 mg orally disintegrating tablets or one 60 mg capsule
    2016
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Background:Dual delayed-release Dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two Dexlansoprazole 30 mg ODTs were compared with one Dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study.Methods:Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two Dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5–10 days after the last dose of study drug.Results:On day 1, peak observed plasma concentration (Cmax) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml...

Sai Nudurupati - One of the best experts on this subject based on the ideXlab platform.

  • Dexlansoprazole and esomeprazole do not affect bone homeostasis in healthy postmenopausal women
    2019
    Co-Authors: Karen E Hansen, Sai Nudurupati, David C. Metz, Jeri W Nieves, Maria Claudia Perez
    Abstract:

    Background & Aims Epidemiological studies have associated proton pump inhibitor (PPI) therapy with osteoporotic fractures, but it is not clear if PPIs directly cause osteoporosis. We evaluated the effect of Dexlansoprazole and esomeprazole on bone turnover, bone mineral density (BMD), true fractional calcium absorption (TFCA), serum and urine levels of minerals, and levels of parathyroid hormone (PTH) in healthy postmenopausal women. Methods We performed a prospective, multicenter, double-blind study of 115 healthy, postmenopausal women (45 to 75 years of age) from November 4, 2010, through August 7, 2014. Women were randomly assigned to groups given Dexlansoprazole (60 mg), esomeprazole (40 mg), or placebo daily for 26 weeks. We measured plasma levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at 0 (baseline), 13, and 26 weeks. Primary outcomes were percent change in P1NP and CTX between weeks 0 and 26. We also measured changes in serum and urine levels of mineral, BMD, PTH (all subjects), and TFCA (n = 30). Results Between baseline and week 26, there were no significant within-group differences in markers of bone turnover; there was a nonsignificant increase in CTX levels in the Dexlansoprazole group (0.12 ng/mL). The esomeprazole and Dexlansoprazole groups had significantly increased levels of P1NP (18.2% and 19.2%, respectively) and CTX (22.0% and 27.4%, respectively) at week 26 compared with the placebo group, although these values remained within normal ranges. There were no statistically significant differences between groups in serum or urine levels of minerals, BMD, or PTH at week 26. PPI therapy did not reduce TFCA. Conclusions In a prospective study of postmenopausal women, we found significant increases in markers of bone turnover in women given PPI therapy compared with women given placebo, but levels remained within the normal reference range. We found no significant differences among groups in changes in BMD, PTH, serum or urine levels of minerals, or TFCA. Our findings indicate that 26 weeks of treatment with a PPI has no clinically meaningful effects on bone homeostasis. Clinicaltrials.gov no: NCT01216293

  • bioavailability of Dexlansoprazole delayed release capsule granules when administered via nasogastric tube or orally via syringe
    2018
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Objective To assess the effect of route of administration on the bioavailability of Dexlansoprazole 60 mg delayed-release capsule granules. Methods One open-label, Phase I, single-dose, 3-period crossover study was conducted in healthy adults. The bioavailability of Dexilant® (Dexlansoprazole) after Dexlansoprazole capsule granules were mixed with water and administered via 16 French nasogastric tube or orally via syringe was compared to administration of the intact capsule in the fasted state, swallowed with water. Blood samples were collected before and after dosing to determine Dexlansoprazole pharmacokinetic parameter estimates and plasma concentrations. Results Similar values for area under the plasma concentration-time curve and observed maximum plasma concentration were achieved when the Dexlansoprazole 60 mg capsule was administered as the intact capsule or when the granules were mixed with water and administered via nasogastric tube or orally via syringe. The primary endpoints of maximum plasma concentration and area under the plasma concentration-time curve demonstrated bioequivalence when assessing these alternative routes of administration. Most adverse events were rated as mild and were comparable irrespective of administration route. Conclusion Systemic exposure to Dexlansoprazole was equivalent regardless of administration route. The Dexlansoprazole capsule was well tolerated.

  • bioavailability of a Dexlansoprazole delayed release orally disintegrating tablet effects of food and mode of administration
    2017
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Background Dexlansoprazole is a proton pump inhibitor (PPI) approved for use in dual delayed-release capsule and orally disintegrating tablet (ODT) formulations. Aim To assess effects of food, water, and route of administration on the bioavailability of Dexlansoprazole 30-mg ODT. Methods Two separate open-label, phase 1, single-dose crossover studies were conducted in healthy adults. In study 1, pharmacokinetic parameters were analyzed in participants receiving Dexlansoprazole ODT in a fed or fasted state with and without water. In study 2, the bioavailability of Dexlansoprazole after administration via oral syringe or nasogastric (NG) tube, or after swallowing intact with water was compared to ODT administration in the fasted state, swallowed without water. Blood samples for determining Dexlansoprazole plasma concentrations and pharmacokinetic parameter estimates were collected before and after dosing. Results Equivalent values for area under the plasma concentration-time curve (AUC) were observed in the fed and fasted states, but the maximum observed plasma concentration (Cmax) was 38% lower in the fed state; therefore, bioequivalence was not achieved. A water rinse following standard ODT administration decreased Dexlansoprazole bioavailability, with lower Cmax and AUC values than when ODT was administered without a water rinse. Bioequivalence was demonstrated when comparing the alternative routes of administration, including via oral syringe or NG tube with standard ODT administration. Unlike with a water rinse, bioequivalence to standard ODT administration (i.e., without water) was demonstrated when swallowing the ODT intact with water. Rates of adverse events were comparable irrespective of administration route in the fasted state (6.7%-9.3%) and were 12% higher in the fed state than in the fasted state. Conclusion The AUC from the Dexlansoprazole ODT was equivalent when administered in the fed and fasted states. Equivalent systemic exposure to Dexlansoprazole was achieved regardless of the administration route.

  • pharmacokinetics and pharmacodynamics of an orally disintegrating tablet formulation of Dexlansoprazole
    2016
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Background:The pharmacokinetics and pharmacodynamics of a novel orally disintegrating tablet (ODT) formulation of delayed-release Dexlansoprazole 30 mg was evaluated versus the Dexlansoprazole 30 mg capsule in this phase I, open-label, multiple-dose, randomized, two-period crossover study.Methods:Healthy adults received daily doses of 30 mg Dexlansoprazole ODT or 30 mg Dexlansoprazole delayed-release capsule for 5 days during two treatment periods, separated by a 7-day washout interval. Blood samples for Dexlansoprazole plasma concentrations and intragastric pH measurements were collected through 24 hours postdose on days 1 and 5 of each period.Results:Bioequivalence between the 30 mg ODT and 30 mg capsule dosage forms was demonstrated by the primary endpoints of Dexlansoprazole peak concentration (Cmax) and systemic exposure (AUC) values contained within the prespecified 90% confidence interval (CI) range of 0.80–1.25. Additional primary endpoints of intragastric mean pH values and percentage of time wit...

  • bioavailability safety and pharmacodynamics of delayed release Dexlansoprazole administered as two 30 mg orally disintegrating tablets or one 60 mg capsule
    2016
    Co-Authors: Michael Kukulka, Sai Nudurupati, Maria Claudia Perez
    Abstract:

    Background:Dual delayed-release Dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two Dexlansoprazole 30 mg ODTs were compared with one Dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study.Methods:Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two Dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5–10 days after the last dose of study drug.Results:On day 1, peak observed plasma concentration (Cmax) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml...

David A Peura - One of the best experts on this subject based on the ideXlab platform.

  • managing gastroesophageal reflux disease comparative efficacy and outcomes of Dexlansoprazole mr
    2015
    Co-Authors: Jeanetta Frye, David A Peura
    Abstract:

    The management of gastroesophageal reflux disease (GERD) has been revolutionized with the development of proton pump inhibitors (PPIs). Unfortunately, due to the inherent pharmacokinetic and pharmacodynamic profiles of conventional PPIs, many patients continue to suffer from symptoms related to GERD despite appropriate use of PPIs. Dexlansoprazole MR is a PPI with a unique dual delayed-release delivery system that has been designed to address the unmet needs in GERD management. Specifically, Dexlansoprazole MR addresses limitations with short plasma half-life and need for meal-associated dosing, characteristic of conventional PPIs. In addition, Dexlansoprazole MR has been shown to be effective in several specific clinical situations. These include coadministration with clopidogrel, healing of all grades of erosive esophagitis, improvement in reflux-related quality of life, step down to once-per-day dosing, and treatment of Helicobacter pylori infections. Furthermore, Dexlansoprazole MR has been found to induce symptom improvement in patients with nonerosive esophageal reflux disease, nocturnal heartburn and GERD-related sleep disturbance, and regurgitation. Overall, Dexlansoprazole MR is a unique and useful tool in the management of GERD.

  • distinguishing the impact of Dexlansoprazole on heartburn vs regurgitation in patients with gastro oesophageal reflux disease
    2013
    Co-Authors: David A Peura, Reema Mody, Betsy Pilmer, Barbara Hunt, Maria Claudia Perez
    Abstract:

    Summary Background Gastro-oesophageal reflux disease (GERD) is characterised by symptomatic heartburn and regurgitation. Treatment with proton pump inhibitors (PPI) effectively decreases heartburn symptoms, but their effects on symptomatic regurgitation are less clear. Aim To determine the impact of PPI therapy on heartburn and regurgitation severity in patients with either non-erosive GERD (NERD) or erosive oesophagitis (EE). Methods Endoscopically-confirmed NERD patients received Dexlansoprazole 30 or 60 mg or placebo in a randomised, blinded, 4-week study. Endoscopically-confirmed EE patients received Dexlansoprazole 60 mg or lansoprazole 30 mg in two 8-week, randomised, blinded healing studies. The Patient Assessment of Upper Gastrointestinal Symptom Severity questionnaire, which includes a heartburn/regurgitation subscale, was administered to assess symptom severity at baseline, and at weeks 2 and 4 of the NERD study and at weeks 4 and 8 during the EE trials. We defined separate subscales for heartburn and regurgitation for this post-hoc analysis. Among patients with both symptoms at baseline, improvements in individual heartburn and regurgitation subscales along with the original combined heartburn/regurgitation subscale were determined. Results In the NERD and EE studies, 661 and 1909 patients, respectively, had both heartburn and regurgitation at baseline. NERD patients receiving Dexlansoprazole 30 and 60 mg experienced significantly greater improvements in symptom severity for both heartburn and regurgitation compared with placebo. EE patients receiving Dexlansoprazole 60 mg had significantly greater improvements in heartburn/regurgitation and heartburn-only subscales at week 4 compared with those receiving lansoprazole. Conclusions Dexlansoprazole appears to be effective in improving both heartburn and regurgitation, and this improvement is maintained for the duration of treatment.

  • the effects of increasing body mass index on heartburn severity frequency and response to treatment with Dexlansoprazole or lansoprazole
    2013
    Co-Authors: David A Peura, Reema Mody, Betsy Pilmer, Barbara Hunt, Maria Claudia Perez
    Abstract:

    Background Higher body mass index (BMI) is a recognised risk factor for gastro-oesophageal reflux disease (GERD). Data regarding the impact of BMI on proton pump inhibitor (PPI) therapy are conflicting.

  • 1152 distinguishing the impact of Dexlansoprazole on heartburn versus regurgitation in patients with nerd or ee
    2012
    Co-Authors: David A Peura, Reema Mody, Barbara Hunt, Betsy L Pilmer, Maria Claudia Perez
    Abstract:

    Purpose: To determine the impact of Dexlansoprazole MR (DEX) on heartburn (HB) and regurgitation severity in nonerosive gastroesphophageal reflux disease (NERD) and erosive esophagitis (EE) patients. Methods: This was a post hoc analysis of patients enrolled in phase 3 studies either assessing the efficacy and safety of DEX vs placebo (PLB) for 24-hour HB relief in NERD or DEX vs lansoprazole (LAN) in EE healing. DEX 30 mg, DEX 60 mg, and PLB were administered to 315, 315, and 317 endoscopically confirmed NERD patients, respectively, in a randomized, double-blind, 4-week study. NERD patients were to have a ≥6 month history of HB. In two 8-week, double-blind, randomized healing studies, 2737 endoscopically confirmed EE patients received DEX 60 mg or LAN 30 mg. In all studies, the Patient Assessment of Upper Gastrointestinal-Symptom Severity questionnaire (PAGISYM) was administered at baseline to assess symptom severity. The PAGI-SYM was also completed at Weeks 2 and 4 of the NERD study, and at Weeks 4 and 8 during the EE healing trials. The PAGI-SYM, a validated questionnaire, includes items assessing severity of HB and regurgitation on a scale of 0 to 5 (no symptoms, mild, moderate, severe and very severe symptoms) yielding a HB/regurgitation subscale. Using the PAGI-SYM questions included in this subscale, we defined separate subscales for HB and regurgitation. Among patients who had both symptoms at baseline (defined as at least mild HB and at least mild regurgitation in the individual subscales), we looked at the change from baseline (CFB) in individual HB and regurgitation subscales along with the original combined HB/regurgitation subscale. Negative CFBs indicate symptom improvement. A CFB of ≥0.55 was considered the minimally important difference for the HB/regurgitation subscale score. Results: In the NERD study, 661 patients had both HB and regurgitation at baseline, as did 1909 patients in the EE study. Table 1 and Table 2 provide the mean CFB in the subscale scores for the NERD and EE patients, respectively. NERD patients receiving DEX 30 and 60 mg experienced significantly greater improvements in symptom severity for both HB and regurgitation compared to PLB. EE patients receiving DEX 60 mg had significantly greater improvements in HB/regurgitation and HB-only subscales at Week 4 compared to those receiving LAN. Conclusions: DEX appears to be effective in improving both the mechanical (regurgitation) and chemical (HB) aspects of GERD symptoms and this improvement is maintained for the duration of treatment. Table 1. NERD

  • Dexlansoprazole mr for the management of gastroesophageal reflux disease
    2011
    Co-Authors: Brian W Behm, David A Peura
    Abstract:

    Dexlansoprazole modified release (MR; Dexilant™), the R-enantiomer of lansoprazole, was approved in the USA in 2009 for the management of erosive esophagitis and nonerosive reflux disease. Dexlansoprazole MR has a unique dual delayed-release delivery system that was designed to address unmet needs that may accompany the use of single-release proton pump inhibitors (PPIs), specifically, their short plasma half-life and requirement for meal-associated dosing. The delivery technology of Dexlansoprazole MR is designed to release the drug in two separate pH-dependent phases, the first in the proximal duodenum and the second in the more distal small intestine. This extends plasma concentration and pharmacodynamic effects of Dexlansoprazole MR beyond those of single-release PPIs and allows for dosing at any time of the day without regard to meals. This added convenience, along with excellent healing of esophagitis and symptom relief, substantiate its use in patients with gastroesophageal reflux disease requiring PPI treatment.

Darcy Mulford - One of the best experts on this subject based on the ideXlab platform.

  • Development of Dexlansoprazole Delayed-Release Capsules, a Dual Delayed-Release Proton Pump Inhibitor
    2019
    Co-Authors: Haiyan Grady, Yusuke Murakawa, Darcy Mulford, Michael Kukulka
    Abstract:

    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.

  • a randomized 2 period crossover design study to assess the effects of Dexlansoprazole lansoprazole esomeprazole and omeprazole on the steady state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers
    2012
    Co-Authors: Andrew L Frelinger, Darcy Mulford, Ronald D Lee, Sai Nudurupati, Anu Nigam, Julie K Brooks, Deepak L Bhatt, Alan D Michelson
    Abstract:

    Objectives The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel. Background Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel. Methods A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (Dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y 12 platelet reactivity index, maximal platelet aggregation to 5 and 20 μmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units. Results Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with Dexlansoprazole or lansoprazole. Similarly, esomeprazole but not Dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > Dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units. Conclusions Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of Dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of Dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole. (A Study of the Effects of Multiple Doses of Dexlansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants; NCT00942175 )

  • the effect of time of day dosing on the pharmacokinetics and pharmacodynamics of Dexlansoprazole mr evidence for dosing flexibility with a dual delayed release proton pump inhibitor
    2010
    Co-Authors: Ronald D Lee, Darcy Mulford, Stuart Atkinson
    Abstract:

    Aliment Pharmacol Ther 31, 1001–1011 Summary Background  Dexlansoprazole MR is a Dual Delayed Release proton pump inhibitor formulated to extend the duration of acid suppression. Aim  To evaluate the pharmacokinetics and pharmacodynamics of Dexlansoprazole MR dosed before 4 different meal times. Methods  In this randomized, open-label, four-way crossover study, 48 healthy subjects received Dexlansoprazole MR 60 mg once daily 30 min before breakfast, lunch, dinner or an evening snack. Pharmacokinetics of Dexlansoprazole MR and intragastric pH were assessed over a 24-h postdose interval on day 5 for each regimen. Results  Absorption was delayed when Dexlansoprazole MR was administered before each regimen relative to breakfast; however, systemic exposures of Dexlansoprazole at all regimens were bioequivalent. There were no statistically significant differences in mean 24-h intragastric pH between dosing before dinner or an evening snack vs. breakfast; however, there was a small (0.2), but statistically significant difference between lunch and breakfast. There was a statistically significant difference of 7 percentage points in the percentage of time intragastric pH was >4 for the snack regimen relative to the breakfast regimen, but there were no statistically significant differences between lunch or dinner compared with breakfast. Conclusion  Dexlansoprazole MR provides comparable acid control when administered at different times of the day.

  • review article dual delayed release formulation of Dexlansoprazole mr a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy
    2009
    Co-Authors: David C. Metz, T Dixit, Majid Vakily, Darcy Mulford
    Abstract:

    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.

  • 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
    2009
    Co-Authors: Majid Vakily, Darcy Mulford, Jingtao Wu, S N Atkinson
    Abstract:

    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.