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

ABSTRACT

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 = 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 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 time curve after administration of dexlansoprazole MR. In each study, doses of dexlansoprazole MR generally produced greater gastric acid suppression than lansoprazole. Based on the exposure–response analysis using combined data from these two trials, the predicted mean 24-h intragastric pH values were 4.06 and 4.35 for the dexlansoprazole MR 30- and 90-mg doses, respectively. The percent of time pH > 4 over 24 h values were 59.2% and 66.7% for dexlansoprazole MR 30 and 90 mg, respectively. No appreciable additional gain in the pharmacodynamic response was predicted for dexlansoprazole MR 120 mg. Despite combining data from two studies to evaluate a broader dose range, this analysis provided a reasonable estimate of the pharmacodynamic parameters and a good characterization of the dexlansoprazole MR exposure–response relationship.

Conclusions: Dexlansoprazole MR, a proton pump inhibitor that uses Dual Delayed Release technology, produced a pharmacokinetic profile with a plasma concentration–time curve characterized by two distinct peaks and an extended duration of pharmacologically active dexlansoprazole concentration in plasma. Exposure–response analysis indicated a progressive increase in the pharmacodynamic response as dexlansoprazole MR doses increased from 30 to 90 mg.

Key words: :

• Dexlansoprazole
• Dual delayed release
• Intragastric pH
• Pharmacodynamics
• Pharmacokinetics
• PK-PD modeling
• Proton pump inhibitor
• TAK-390

Acknowledgments

Declaration of interest: Funding was provided by Takeda Pharmaceuticals Research & Development, Inc. Majid Vakily, Jingtao Wu, Stuart Atkinson, and Darcy Mulford are employees of Takeda. (At the time of study conduct and analysis they were employees of TAP Pharmaceutical Products Inc., now a part of Takeda.) Weijiang Zhang was an employee of TAP Pharmaceutical Products Inc. at the time of the study conduct and analysis. The authors acknowledge Galen Witt for his technical assistance, and MDS Pharma Services Inc., Lincoln, NE, USA for analyzing the samples. They also acknowledge assistance in manuscript preparation provided by Eileen Gallagher of Complete Healthcare Communications, Inc., Chadds Ford, PA, USA.

Notes

* Data from Study 1, TAP Study No. P104-071, were presented as a poster at Digestive Disease Week, Washington, DC, May 19–24, 2007; the abstract was subsequently published in Gastroenterology 2007;132 (Suppl 52):A487