DWP14012 was well tolerated, and showed a rapid and long-lasting gastric acid suppression effect in healthy subjects. These results justify further investigation of DWP14012 in patients with acid-related disorders.

Funding information Daewoong Pharmaceutical CompanyAims: DWP16001 is a novel sodium-glucose cotransporter-2 inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics, pharmacodynamics and safety of DWP16001 after single and multiple doses in healthy subjects.Methods: A randomized, double-blind, placebo-and active-controlled, single-and multiple-dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0 or 5.0 mg) or multiple doses (0.1, 0.3, 0.5, 1.0 or 2.0 mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10 mg or placebo at a ratio of 8:2:2. Serial blood and interval urine samples were collected for the pharmacokinetic and pharmacodynamic analyses. The safety and tolerability of DWP16001 were also assessed.Results: A dose-dependent increase in the urinary glucose excretion was observed after a single dose, and the steady state urinary glucose excretion was 50-60 g/d after multiple doses in the dose range of 0.3-2.0 mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0-3.0 hours, and it exhibited a mean elimination half-life of 13-29 hours. The systemic exposure to DWP16001 increased proportionally with multiple dose administrations in the range of 0.1-2.0 mg. DWP16001 was well tolerated in all dose groups. Conclusion: DWP16001 induced glucosuria in a dose-dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated in single oral doses of up to 5.0 mg and in multiple oral doses of up to 2.0 mg.

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We hypothesized that the pharmacodynamic (PD) characteristics of metformin would change with inhibition of the multidrug and toxin extrusion (MATE) transporter, which mediates renal elimination of metformin. Twenty healthy male subjects received two doses (750/500 mg) of metformin, with and without 50 mg of pyrimethamine (a potent MATE inhibitor), with 1 week of washout in between each dose. The PD characteristics of metformin were assessed using oral glucose tolerance tests (OGTTs) before and after the metformin dose. Metformin concentrations in plasma and urine were determined using liquid chromatography-electrospray ionization-tandem mass spectrometry. When metformin was co-administered with pyrimethamine, its area under the concentration-time curve from 0 to 12 h was 2.58-fold greater (p < 0.05), whereas the antihyperglycaemic effects of metformin were decreased. The mean differences (90% confidence interval) in mean and maximum serum glucose concentrations and in 2-h-post-OGTT serum glucose concentration were -0.6 (-1, -0.2), -0.9 (-1.6, -0.3) and -0.5 (-1.1, 0.1) mmol/l, respectively. These findings indicate that the response to metformin is not only related to the plasma exposure of metformin but is also related to other factors, such as inhibition of uptake transporters and the gastrointestinal-based pharmacology of metformin.

This study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of vutiglabridin, a potential anti‐obesity treatment under development, for the first time in humans. A randomized, placebo‐controlled, single‐ and multiple‐ascending dose study (SAD and MAD, respectively) was performed in healthy Koreans and Whites. Subjects randomly received a single oral dose of 30–720 mg vutiglabridin or placebo at a ratio of 8:2 in the SAD study or 240–480 mg vutiglabridin or placebo once daily for 14 days in the MAD study. Food effect was also evaluated in 240 mg single dose group. Pharmacokinetics were evaluated through plasma concentrations, and pharmacodynamic biomarkers related to obesity or inflammation were analyzed. Safety and tolerability were assessed throughout the study. Single and multiple doses of vutiglabridin were generally well‐tolerated. The pharmacokinetic parameters show less than dose‐proportionality increase, and plasma concentrations increased more than two‐fold after multiple administrations. The mean half‐life of Koreans and Whites in the MAD study was 110 and 73 h, respectively. The systemic exposure of vutiglabridin was significantly increased when taken with a high‐fat meal, and the systemic exposure was lower in Whites than in Koreans. Vutiglabridin was well‐tolerated in healthy Koreans and Whites. The plasma concentration increased less than the dose‐proportionality manner. These results justify further investigation of vutiglabridin in patients with obesity.