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Hae Won Lee,1,2 Woo Youl Kang,1,2 Wookjae Jung,1,2 Mi-Ri Gwon,1,2 Kyunghee Cho,3 Young-Ran Yoon,1,2 Sook Jin Seong1,2 1Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; 2Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea; 3Analytical Research Division, Biocore Co. Ltd., Seoul, 08511, Republic of KoreaCorrespondence: Young-Ran Yoon, Department of Molecular Medicine, School of Medicine, Kyungpook National University, 130 Dongdeok-Ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82 53-420-4950, Fax +82 53-420-5218, Email yry@knu.ac.kr Sook Jin Seong, Department of Clinical Pharmacology, School of Medicine, Kyungpook National University, 130 Dongduk-Ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82 53-200-6351, Fax +82 53-420-5218, Email wintersj@knu.ac.krBackground: YYD601 was developed as a novel dual delayed release (DDR) formulation of esomeprazole to prolong the plasma esomeprazole concentration and extend the duration of acid suppression.Purpose: The pharmacokinetic (PK) and pharmacodynamics (PD) characteristics of YYD601 after single and multiple oral administrations were investigated in healthy Korean adults under fasting and fed conditions, and compared with the original esomeprazole capsule.Methods: In the single-center, randomized, open-label, parallel-design, two-period study, thirty two volunteers were enrolled into four dosing groups, including esomeprazole 40-mg (group A), YYD60130-mg (group B), YYD601 40-mg (group C), and YYD601 60-mg (group D) once daily for 5 days. Blood samples were collected for PK analysis, before and up to 24 h after dosing. For PD characteristics of YYD601, the percentages of time with intragastric pH > 4 over a 24-h period and during night-time following multiple oral administrations were evaluated.Results: A total of 27 subjects completed the study. YYD601 showed a dual-peak PK profile under fasting condition, with delayed Tmax, compared with conventional formulation. There were no significant differences in the AUC values adjusted for dose between the three YYD601 dosage groups and the conventional esomeprazole 40 mg. The esomeprazole AUC following single and multiple administration decreased with food intake by approximately 33%. YYD601 showed a linear pharmacokinetic profile in the dose range studied. There was no statistically significant difference in increase in mean percentage of time with intragastric pH > 4 for 24-hour and during night-time between the three different doses of YYD601 and the conventional formulation. The treatments were well-tolerated during the study and no serious adverse events were observed.Conclusion: YYD601 30 mg has a comparable effect on gastric acid inhibition as conventional esomeprazole 40 mg following once daily oral administration. Single and multiple oral dosing of YYD601 up to 60 mg were safe and well-tolerated throughout the study.Clinical Trial Registry: http://clinicaltrials.gov, NCT03558477 (date of registration: June 15, 2018; study period: between October 2017 and February 2018).Keywords: esomeprazole, dual delayed release, pharmacokinetics, pharmacodynamics

Michael Kukulka,1 Sai Nudurupati,2 Maria Claudia Perez3 1Department of Clinical Pharmacology, Takeda Development Center Americas, Inc., Deerfield, IL, USA; 2Department of Analytical Sciences, Takeda Development Center Americas, Inc., Deerfield, IL, USA; 3Department of Clinical Science, Takeda Development Center Americas, Inc., Deerfield, IL, USA 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. Keywords: TAK-390MR, dexlansoprazole, dual delayed release, pharmacokinetics, proton pump inhibitor

Dexlansoprazole MR is a modified release formulation of the R-enantiomer of lansoprazole, which employs a novel Dual Delayed Release (DDR) technology. Pharmacokinetic studies have shown that the DDR technology provides a two peaks drug release, accuring 1-2 hours and 4-5 hours after dosing, leading to an extended duration of therapeutic plasma drug concentrations compared with conventional delayed release lansoprazole. Dexlansoprazole MR 30 and 60 mg provided superior intragastric pH control compared to that obtained with lansoprazole 15 mg and 30 mg once daily dosing. Dexlansoprazole can be taken without regard to food. The drug has been shown to be as efficacious as lansoprazole in healing, and superior to placebo in maintaining healing, of erosive esophagitis. Dexlansoprazole appears to be well tolerated with a comparable safety profile to lansoprazole. Overall, dexlansoprazole DR has an interesting pharmacokinetic profile and is effective and well tolerated in the healing and maintenance of erosive esophagitis and in the treatment of GERD. Nevertheless in the absence of head-to-head comparison there is no mean to recommend its use preferentially to other PPIs. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and pharmacokinetic profile of dexlansoprazole modified-release (MR) capsules in pediatric patients with symptomatic gastroesophageal reflux disease (GERD)., Methods: This Phase I, open-label study enrolled male and female patients (1 to 11 years of age) with GERD. Patients received dexlansoprazole MR 15 mg, 30 mg, or 60 mg (according to weight) once daily for 7 days. Blood samples for the measurement of plasma dexlansoprazole concentrations were collected for 24 hours after the day 7 dose. Dexlansoprazole plasma concentrations and pharmacokinetic parameters were summarized by dose group. Safety assessments included adverse events (AEs), clinical laboratory evaluations, fasting gastrin concentrations, physical examinations, electrocardiograms, and vital signs., Results: Thirty-six patients received study drug (12 per dose group), and 31 had evaluable pharmacokinetic data. There was a significant effect of weight on dose-normalized area under the curve (AUC, P=0.003) and dose-normalized maximum plasma concentration (Cmax) (P=0.013), indicating that for a given dose, dexlansoprazole exposure decreases as body weight increases. After adjusting for body weight, both dexlansoprazole Cmax and AUC increased in an approximately dose-proportional manner with increasing dexlansoprazole dose. A total of ten of 36 patients reported at least one treatment-emergent AE, with most events considered mild in intensity. The most common AEs were vomiting, abdominal pain, diarrhea, and nausea., Conclusion: In 1- to 11-year-old patients with symptomatic GERD, weight-adjusted dexlansoprazole AUC and Cmax increased approximately dose-proportionally. However, for a given dose, dexlansoprazole exposure decreased with increasing body weight. Dexlansoprazole MR was well tolerated, and the incidence of AEs did not increase with increasing dose.