Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium

摘要

Objective: Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor. Methods: In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 μg gly-copyrronium was inhaled alone and on Day 4 of a 6-day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout ci-metidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrro-nium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast), and renal clearance (CLr) of glycopyrronium. Results: Cimeti-dine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyr-ronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12-1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70-0.85). C max was not affected. Both treatments were safe and well tolerated without any deaths or severe adverse events. Conclusion: Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.