Target-controlled infusion and population pharmacokinetics of landiolol hydrochloride in gynecologic patients

Purpose: We previously determined the pharmacokinetic (PK) parameters of landiolol in healthy male volunteers. In this study, we evaluated the usefulness of target-controlled infusion (TCI) of landiolol hydrochloride and determined PK parameters of landiolol in gynecologic patients. Methods: Nine patients who were scheduled to undergo gynecologic surgery were enrolled. After inducing anesthesia, landiolol hydrochloride was administered at the target plasma concentrations of 500 and 1,000 ng/mL for each 30 min. A total of 126 data points of plasma concentration were collected from the patients and used for the population PK analysis. Furthermore, a population PK model was developed using the nonlinear mixed-effect modeling software. Results: The patients had markedly decreased heart rates (HRs) at 2 min after the initiation of landiolol hydrochloride administration; however, their blood pressures did not markedly change from the baseline value. The concentration time course of landiolol was best described by a 2-compartment model with lag time. The estimate of PK parameters were total body clearance (CL) 34.0 mL/min/kg, distribution volume of the central compartment (V₁) 74.9 mL/kg, inter-compartmental clearance (Q) 70.9 mL/min/kg, distribution volume of the peripheral compartment (V₂) 38.9 mL/kg, and lag time (ALAG) 0.634 min. The predictive performance of this model was better than that of the previous model. Conclusion: TCI of landiolol hydrochloride is useful for controlling HR, and the PK parameters of landiolol in gynecologic patients were similar to those in healthy male volunteers and best described by a 2-compartment model with lag time.