Population Plasma and Urine Pharmacokinetics of Ivabradine and its Active Metabolite in Korean Healthy Volunteers

Aims: Ivabradine, a selective inhibitor of the pacemaker current (If), is used for heart failure and coronary heart disease, and mainly metabolized to S18982 (1). The purpose of this study was to explore the pharmacokinetics (PK) of ivabradine and S18982 in healthy Korean volunteers.

Methods: Subjects in a phase I study were randomized to receive 2.5, 5, or 10 mg of ivabradine administered every 12 hours for 4.5 days, and serial plasma and urine concentrations of ivabradine and S18982 were measured using validated LC/MS-MS. Plasma and urine PK were analyzed by nonlinear mixed effect modeling implemented in NONMEM (version 7.3).

Results: The plasma PK of ivabradine was best described by a two-compartment model with mixed zero- and first-order absorption, linked to a two-compartment model for S18982. The final PK model described plasma concentration and cumulative amount excreted urine of ivabradine and S18982, reasonably well. The introduction of inter-occasional variabilities and period as covariate into absorption related parameters improved the model fit. Urine data have been applied to estimate renal and non-renal clearance, enabling a more detailed description of the elimination process.

Conclusion: We developed a population PK model describing the plasma and urine PK of ivabradine and S18982 in healthy Korean adult males. This model might be useful for predicting the plasma and urine PK of ivabradine, potentially helping to identify the optimal dosing regimens in various clinical situations.

References:

1. Ragueneau I, Laveille C, Jochemsen R, et al: Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin Pharmacol Ther. 1998; 64(2):192-203.