Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 56, Issue 4, Pages 439-449Publisher
WILEY
DOI: 10.1002/jcph.614
Keywords
ivabradine; S18982; plasma pharmacokinetics; urine pharmacokinetics; NONMEM
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Funding
- Institut de Recherches Internationales Servier (IRIS), France
- Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI14C1061, HI14C1090]
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Ivabradine, a selective inhibitor of the pacemaker current (I-f), is used for heart failure and coronary heart disease and is mainly metabolized to S18982. The purpose of this study was to explore the pharmacokinetics (PK) of ivabradine and S18982 in healthy Korean volunteers. Subjects in a phase I study were randomized to receive 2.5, 5, or 10mg of ivabradine administered every 12 hours for 4.5 days, and serial plasma and urine concentrations of ivabradine and S18982 were measured. The plasma PK of ivabradine was best described by a 2-compartment model with mixed 0- and first-order absorption, linked to a 2-compartment model for S18982. The introduction of interoccasional variabilities and period as covariate into absorption-related parameters improved the model fit. Urine data have been applied to estimate renal and nonrenal clearance, enabling a more detailed description of the elimination process. 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.
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