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

Figures & data

Figure 1 Sample times, target concentration, and predicted concentrations after infusion using the target-controlled infusion system according to the previous parameters in healthy males.

Note: The predicted plasma concentration was shifted toward the left parallel for 0.820 minutes because lag time was not used. Honda et al’s parameter was used.⁶ Copyright © 2014. Japanese Society of Anesthesiologists. Reproduced from Kunisawa T, Yamagishi A, Suno M, et al. Target-controlled infusion and population pharmacokinetics of landiolol hydrochloride in gynecologic patients. J Anesth. Epub 2014 Sep 4.⁴

Figure 2 Observed and predicted concentrations of landiolol.

Notes: The thin solid line shows the concentrations predicted using the previous parameters,⁶ and the bold solid line shows the concentrations predicted using the present parameters. The predicted plasma concentration was shifted parallel toward the left for 0.820 minutes because lag time was not used. Data are expressed as mean ± standard deviation.
Abbreviation: pCp, predicted plasma concentration.

Figure 3 Hemodynamic values.

Notes: SBP, DBP, and HR are shown during and 20 minutes after the administration of landiolol hydrochloride. In comparison with the baseline values, SBP was lower at five time points. DBP values after administration did not change significantly. The HR significantly decreased 2 minutes after starting administration of landiolol hydrochloride. Data are expressed as mean ± standard deviation. *P<0.05 when compared with the base value (0 minutes).
Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure.

Table 1 Demographics and baseline clinical characteristics of the study patients

Baseline characteristics	Mean (SD) or n	Range
Sex (male/female)	6/2	–
Body weight (kg)	58.9 (10.9)	40.4–71.8
Lean body mass (kg)	46.4 (8.1)	32.0–53.7
Height (cm)	159 (7)	147–170
Age (years)	73 (7)	64–84
Albumin level (g/dL)	3.8 (0.5)	2.8–4.5
AST level (IU/L)	18 (5)	12–26
ALT level (IU/L)	16 (9)	7–34
Total bilirubin level (mg/dL)	0.6 (0.3)	0.2–1.0
Cholinesterase level (IU/L)	287 (92)	199–465
BUN level (mg/dL)	21 (7)	10–32
Serum creatinine level (mg/dL)	1.00 (0.52)	0.42–2.07

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; SD, standard deviation.

Figure 4 OBS versus PRED from the present model.

Note: The solid line represents the unit line.
Abbreviations: OBS, observed concentrations; PRED, predicted concentrations.

Figure 5 Diagnostic plots of CWRES versus PRED (A) or time after beginning of infusion (B).

Note: The horizontal line represents the zero level.
Abbreviations: CWRES, conditional weighted residuals; PRED, predicted concentrations.

Figure 6 Visual predictive check of the present model.

Notes: Open circles represent the observed concentration. The solid line represents the median of the prediction interval. Dotted lines represent the 5% and 95% prediction intervals.

Figure 7 Percent PE versus time after beginning of infusion.

Notes: PE in (A) and (B) were calculated using the previous and present models, respectively. The horizontal line represents the zero level.
Abbreviation: PE, performance errors.

Table 2 Pharmacokinetic parameter estimates of landiolol from the population model

Fixed effect	Estimates of the model parameters
	Healthy male volunteers, mean ± SE	Patients with peripheral arterial disease, mean ± SE
TVCL (mL/min/kg)	36.6±1.23	30.7±2.08
TVV1 (mL/kg)	101±8.83	65.0±4.97
TVQ (mL/min/kg)	16.1±3.70	48.3±16.4
TVV2 (mL/kg)	55.6±6.05	54.4±4.54
TVALAG (min)	0.820±0.0613	0.633±0.000173
Interindividual variability	Mean ± SE (CV%)	Mean ± SE (CV%)
ωCL^2	0.0475±0.00874 (21.8)	0.0183±0.00768 (13.5)
ωV1^2	0.214±0.0426 (46.3)	–
Residual variability	Mean ± SE (CV%)	Mean ± SE (CV%)
σ^2	0.0490±0.00757 (22.1)	0.0773±0.0234 (27.8)

Note: Landiolol were administrated using the parameter in Honda et al.⁶

Abbreviations: σ², residual variability; ω_CL², interindividual variability in CL; ω_V1², interindividual variability in V₁; CL, total body clearance; CV, coefficient of variation; SE, standard error; TVALAG, typical value of the lag time; TVCL, typical value of total body clearance; TVQ, typical value of the intercompartmental clearance; TVV₁, typical value of the distribution volume of the central compartment; TVV₂, typical value of the distribution volume of the peripheral compartment; V₁, distribution volume of the central compartment.

Table 3 Comparison of prediction performance between the previous and present models

	MDPE	MDAPE
Previous model	26.7 (0.3, 53.3)	36.4 (21.4, 58.2)
Present model	7.1 (−5.3, 17.1)	13.2 (7.0, 19.3)

Note: Data are expressed as median (25th, 75th percentiles).

Abbreviations: MDAPE, median absolute performance error; MDPE, median performance error.

HondaNNakadeSKasaiHPopulation pharmacokinetics of landiolol hydrochloride in healthy subjectsDrug Metab Pharmacokinet200823644745519122339

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KunisawaTYamagishiASunoMTarget-controlled infusion and population pharmacokinetics of landiolol hydrochloride in gynecologic patientsJ Anesth Epub201494

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