Population pharmacokinetics of landiolol hydrochloride in healthy subjects.
Landiolol hydrochloride is a newly developed cardioselective, ultra short-acting beta(1)-adrenergic receptor blocking agent used for perioperative arrhythmia control. The objective of this study was to characterize the population pharmacokinetics of landiolol hydrochloride in healthy male subjects. A total of 420 blood concentration data points collected from 47 healthy male subjects were used for the population pharmacokinetic analysis. NONMEM was used for population pharmacokinetic analysis. In addition, the final pharmacokinetic model was evaluated using a bootstrap method and a leave-one-out cross validation method. The concentration time course of landiolol hydrochloride was best described by a two-compartment model with lag time. The final parameters were total body clearance (CL: 36.6 mL/min/kg), distribution volume of the central compartment (V1: 101 mL/kg), inter-compartmental clearance (16.1 mL/min/kg), distribution volume of the peripheral compartment (55.6 mL/kg), and lag time (0.82 min). The inter-individual variability in the CL and V1 were 21.8% and 46.3%, respectively. The residual variability was 22.1%. Model evaluation by the two different methods indicated that the final model was robust and parameter estimates were reasonable. The population pharmacokinetic model for landiolol hydrochloride in healthy subjects was developed and was shown to be appropriate by both bootstrap and leave-one-out cross validation methods.
Honda
Naoki
N
Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki, Japan.
Nakade
Susumu
S
Kasai
Hidefumi
H
Hashimoto
Yoshitaka
Y
Ohno
Tomoya
T
Kitagawa
Junsaku
J
Yamauchi
Akinori
A
Hasegawa
Chihiro
C
Kikawa
Shinichi
S
Kunisawa
Takayuki
T
Tanigawara
Yusuke
Y
Miyata
Yasuyuki
Y
D000328:Adult; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics*; D010865:Pilot Projects; D011153:Population; D015203:Reproducibility of Results; D014508:Urea / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
D009025:Morpholines; C077049:landiolol; D014508:Urea