Safety, tolerability, pharmacodynamics and pharmacokinetics of DWP14012, a novel potassium-competitive acid blocker, in healthy male subjects.

BACKGROUND: A novel potassium-competitive acid blocker, DWP14012, is in clinical development as a potential alternative to proton pump inhibitors for the treatment of acid-related diseases. AIMS: To evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of DWP14012 in humans. METHODS: A randomised, double-blind, double-dummy, placebo- and active-controlled, single- and multiple-ascending dose (SAD and MAD, respectively) study was conducted in healthy male subjects without Helicobacter pylori infection. Subjects randomly received a single oral dose of 10-320 mg DWP14012, esomeprazole (active comparator) or placebo in the SAD study (n = 72) and once daily doses of 20-160 mg DWP14012, esomeprazole or placebo for 7 days in the MAD study (n = 48; 8:2:2). Tolerability was evaluated using a microRNA-122 assay. Pharmacodynamics were evaluated through 24-hour gastric pH monitoring, and pharmacokinetics were evaluated plasma and urine DWP14012 concentrations. RESULTS: DWP14012 was generally well tolerated. The liver toxicity of DWP14012 was not higher than that of placebo after multiple oral administrations. DWP14012 showed rapid and sustained suppression of gastric acid secretion for 24 hours after dosing. Clear dose-response and exposure-response relationships were observed. Plasma concentrations of DWP14012 increased in a dose-proportional manner in the MAD study, whereas in the SAD study, DWP14012 did not significantly accumulate in the plasma. CONCLUSIONS: 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.

Aspirin decreases systemic exposure to clopidogrel through modulation of P-glycoprotein but does not alter its antithrombotic activity.

Decreased oral clopidogrel absorption caused by induction of intestinal permeability glycoprotein (P-gp) expression after aspirin administration was observed in rats. This study evaluated the effect of aspirin coadministration on the pharmacokinetics/pharmacodynamics of clopidogrel in humans. A single 75-mg dose of clopidogrel was orally administered before and after 2 and 4 weeks of once-daily 100-mg aspirin administration in 18 healthy volunteers who were recruited based on CYP2C19 and PON1 genotypes. Plasma concentrations of clopidogrel and its active metabolite, H4, and relative platelet inhibition (RPI) were determined. The P-gp microRNA miR-27a increased by up to 7.67-fold (P = 0.004) and the clopidogrel area under the concentration-time curve (AUC) decreased by 14% (P > 0.05), but the AUC of H4 remained unchanged and RPI increased by up to 15% (P = 0.002) after aspirin administration. These findings indicate low-dose aspirin coadministration may decrease clopidogrel bioavailability but does not decrease its efficacy.