Population plasma and urine pharmacokinetics of ivabradine and its active metabolite S18982 in healthy Korean volunteers.
Ivabradine, a selective inhibitor of the pacemaker current (If ), 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 10 mg 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.
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Hee Youn
HY
Choi
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kyun-Seop
KS
Bae
Department of Clinical Pharmacology, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.
Sang-Heon
SH
Cho
Department of Clinical Pharmacology, Busan Paik Hospital, Busan, Korea.
Jong-Lyul
JL
Ghim
Clinical Trials Center, Pusan National University, Busan, Korea.
Sangmin
S
Choe
Department of Clinical Pharmacology, Busan Paik Hospital, Busan, Korea.
Jin Ah
JA
Jung
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Hyeong-Seok
HS
Lim
D000328:Adult; D044466:Asian People; D001552:Benzazepines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D000077550:Ivabradine; D007723:Korea; D008297:Male; D008954:Models, Biological; D010949:Plasma / Q000378:metabolism*; D014556:Urine / Q000737:chemistry*; D055815:Young Adult
D001552:Benzazepines; D000077550:Ivabradine
NONMEM; S18982; ivabradine; plasma pharmacokinetics; urine pharmacokinetics