Target-controlled infusion and population pharmacokinetics of landiolol hydrochloride in patients with peripheral arterial disease

Abstract

Purpose

We previously determined the pharmacokinetic (PK) parameters of landiolol in healthy male volunteers and gynecological patients. In this study, we determined the PK parameters of landiolol in patients with peripheral arterial disease.

Methods

Eight patients scheduled to undergo peripheral arterial surgery were enrolled in the study. After inducing anesthesia, landiolol hydrochloride was administered at target plasma concentrations of 500 and 1,000 ng/mL for 30 minutes each. A total of 112 data points of plasma concentration were collected from the patients and used for the population PK analysis. A population PK model was developed using a nonlinear mixed-effect modeling software program (NONMEM).

Results

The patients had markedly decreased heart rates at 2 minutes after initiation of landiolol hydrochloride administration; however, systolic blood pressures were lower than the baseline values at only five time points. The concentration time course of landiolol was best described by a two-compartment model with lag time. The estimates of PK parameters were as follows: total body clearance, 30.7 mL/min/kg; distribution volume of the central compartment, 65.0 mL/kg; intercompartmental clearance, 48.3 mL/min/kg; distribution volume of the peripheral compartment, 54.4 mL/kg; and lag time, 0.633 minutes. The predictive performance of this model was better than that of the previous model.

Conclusion

The PK parameters of landiolol were best described by a two-compartment model with lag time. Distribution volume of the central compartment and total body clearance of landiolol in patients with peripheral arterial disease were approximately 64% and 84% of those in healthy volunteers, respectively.

Keywords:

• landiolol hydrochloride
• pharmacokinetics
• target-controlled infusion
• peripheral arterial disease
• TCI
• pharmacokinetic parameters
• PAD

Acknowledgments

This work was supported by JSPS KAKENHI Grant Number 23791680. Support was also provided from institutional and/or departmental sources. Pure landiolol hydrochloride and ONO-SA-137 for the internal standards were kindly provided by the Ono Pharmaceutical Co., Ltd., (Osaka, Japan).

Disclosure

Susumu Nakade and Naoki Honda, who conducted the population pharmacokinetic analysis using fixed data supplied by Asahikawa Medical University, are employees of the Ono Pharmaceutical Co., Ltd. (Osaka, Japan), which sells landiolol hydrochloride in Japan. The authors report no other conflicts of interest in this work.