Download A Pharmacokinetic and Pharmacodynamic Study of Intravenous

Original Article
Acta Cardiol Sin 2014;30:298-307
Cardiac Pharmacology
A Pharmacokinetic and Pharmacodynamic Study
of Intravenous Levosimendan in Healthy Chinese
Volunteers and Ethnic Comparisons
Kai-Min Chu,1 Oliver Yoa-Pu Hu2 and Jun-Ting Liou1
Background: The objective of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous
levosimendan and the metabolites (OR1855 and OR1896) in healthy Chinese male subjects and to post hoc
compare with Caucasian subjects.
Methods: One single 2 mg dose of levosimendan was infused intravenously over 10 minutes to each of 14 healthy
male subjects. Plasma levosimendan was analyzed by high performance liquid chromatography. Pharmacodynamics
was evaluated using echocardiography.
Results: The Cmax (peak concentration) and AUC¥ (area under the curve from time 0 to infinity) of levosimendan of
Chinese subjects were significantly higher than for Caucasian subjects as 256.1 ± 37.8 (mean ± SD) vs. 142.1 ± 17.5
ng/mL and 207.5 ± 35.2 vs. 117.0 ± 17.0 hr×ng/mL, respectively. The clearance of Chinese subjects was significantly
lower than Caucasian subjects at 9.9 ± 1.8 vs. 17.4 ± 2.7 L/hr, respectively. The elimination half-life of Chinese
subjects was significantly longer than for Caucasian subjects (1.18 ± 0.18 vs. 0.76 ± 0.10 hr, respectively). Chinese
subjects eliminated levosimendan significantly slower than Caucasian subjects, leading to a higher exposure of
levosimendan in Chinese subjects. However, this higher exposure did not significantly change the most
pharmacodynamic properties of levosimendan except for ejection fraction (EF). The EF increased 12.2 ± 11.4% in
Chinese subjects 20 min after the end of intravenous infusion, which was significantly lower than Caucasian
subjects with EF increased by 22.7 ± 7.0%.
Conclusions: The intravenous levosimendan in healthy Chinese volunteers was safe, and well-tolerated with
significant inotropic effect. The clearance of levosimendan of Chinese subjects was significantly lower and
elimination half-life longer than Caucasian subjects.
Key Words:
Chinese · Ethnic comparison · Levosimendan · Pharmacodynamics · Pharmacokinetics ·
Volunteer
INTRODUCTION
patients with acute congestive heart failure (CHF) and
have demonstrated short-term hemodynamic support
and symptomatic relief. Clinical trials with positive
inotropic agents in patients with CHF have corroborated
that these agents provide an improvement in the symptoms; however, they may also increase the mortality
rate.1,2
Dobutamine is the agent most frequently used to
treat hemodynamic disturbances resulting from episodes of a worsening heart failure. Side effects of dobutamine observed in clinical trials include tachyphy-
Positive inotropic agents have been used to treat
Received: May 31, 2013
Accepted: October 4, 2013
1
Division of Cardiology, Department of Internal Medicine, Tri-Service
General Hospital, National Defense Medical Center; 2School of
Pharmacy, National Defense Medical Center, Taipei, Taiwan.
Address correspondence and reprint requests to: Dr. Kai-Min Chu,
Division of Cardiology, Department of Internal Medicine, Tri-Service
General Hospital, National Defense Medical Center, No. 325, Sec. 2,
Cheng-Kung Rd., Nei-Hu District, Taipei 114, Taiwan. Tel: 886-28792-7160; Fax: 886-2-6601-2656; E-mail: [email protected]
Acta Cardiol Sin 2014;30:298-307
298
Pharmacokinetics and Pharmacodynamics of Levosimendan
of 2 days), and are detectable for at least 10 days.15
The efficacy and safety of levosimendan have been
investigated in several studies. Levosimendan has been
shown to increase cardiac output and ejection fraction
in healthy subjects. 10 In addition, levosimendan decreased pulmonary capillary wedge pressure and peripheral vascular resistance, and increased stroke volume and cardiac output dose-dependently in patients
with heart failure.12,16,17 Use of the recommended dose
of levosimendan (0.05-0.2 mg/kg/min) produced a modest increase in heart rate, which was long-lasting.13,15
In general, the safety profile was related to the
pharmacology of levosimendan. The most frequent adverse drug reactions were headache and hypotension
(both about 6%).18-20 Other less common adverse drug
reactions included nausea and dizziness (both about
2%), atrial fibrillation and ventricular tachycardia (both
about 1%). Adverse events related to arrhythmias and
myocardial ischemia were significantly less frequently
reported with levosimendan than with dopamine.
All of the clinical data thus far have been collected
in Caucasian subjects. It is considered important to assess the pharmacokinetic and pharmacodynamic effects
associated with the intravenous administration of levosimendan in Chinese subjects. This study was the first
levosimendan study in the Chinese population. The objective of this study was to assess the pharmacokinetics,
pharmacodynemics and safety effects of intravenous
levosimendan and the metabolites (OR1855 and OR1896)
in healthy Chinese male subjects.
laxis, an increasing heart rate, cardiac arrhythmias and
increasing incidences of myocardial ischemia.3,4 Some of
these side effects have also been observed with adenosine monophosphate-dependent inotropes (phosphodiesterase inhibitors) such as amrinone, milrinone, or
enoximone.5 Due to lack of positive long-term patient
outcomes following treatment, the overall benefits of
such agents are questionable.
Levosimendan is an intravenously administered
calcium-sensitizing agent indicated for the short-term
(24 hour) treatment of decompensated chronic heart
failure. In vitro and in vivo studies have demonstrated
that levosimendan increases myocardial contractility,
lowers cardiac filling pressures, and dilates peripheral
and coronary blood vessels.6
The main mechanism of action of levosimendan is
calcium sensitization of the contractile protein in cardiac muscle. The effect is obtained by calcium-dependent binding of the drug to cardiac troponin C. It increases the contractile force of cardiomyocytes. Due to
calcium dependency, levosimendan does not impair relaxation. Additionally, levosimendan opens the ATPsensitive potassium channels in both vascular and cardiac tissues, thereby producing vasodilatory and anti
ischemic effects.7-9
The pharmacokinetics (PK) of levosimendan are
linear with plasma concentrations increasing in a doseproportional manner following a single bolus intravenous infusion of doses ranging from 0.2 to 5.0 mg in
healthy volunteers and patients with CHF. 9 Levosimendan is rapidly distributed to tissues and 95-98% of
the drug in plasma is bound to plasma proteins, mainly
albumin.10-12 The parent drug has a half-life (t1/2) of approximately one-hour with steady-state concentrations
reached within four hours of initiating a continuous infusion, without a preceding loading dose.9
Two metabolites (OR1855 and OR1896) of levosimendan have been identified in human plasma following intravenous infusion.13,14 Only the acetylated metabolite OR1896 is pharmacologically active, and only
about 5% of the levosimendan dose is metabolized to
OR1896. It is formed and eliminated slowly, with an
elimination half-life of approximately 80 hours.15 Following a continuous 24-hour infusion of levosimendan (0.1
to 0.4 mcg/kg/min), peak concentrations of these active
metabolites are reached within one to four days (mean
MATERIALS AND METHODS
Study design and plan
This was a Phase 1, single-dose, open-label, and
single-center study. In vitro protein binding assay and
distribution kinetics assay were also conducted.
Fourteen healthy male Chinese subjects were enrolled in this study. All subjects were determined to be
in good health on the basis of history, physical examination, urinalysis, blood chemistry, chest roentgenogram
and electrocardiogram. None of the subjects had a history of cardiovascular, renal, hepatic, gastrointestinal,
respiratory, hematological, metabolic or other diseases
that could affect the absorption, distribution, meta299
Acta Cardiol Sin 2014;30:298-307
Kai-Min Chu et al.
sequent procedures were the same as noted in the
above two paragraphs.
bolism, or excretion of the study drug. None had a
history of drug or alcohol abuse, donation or loss of 550
ml or more blood within 8 weeks prior to study, or use
of tobacco or nicotine-containing products within the
6-month period prior to our study. The protocol was
approved by the Human Subject Institutional Review
Board. The study was carried out in accordance with
those parameters as established by the Declaration of
Helsinki. Written informed consent was obtained after
the purpose, procedures, and risks of the study had
been explained to the volunteers. The volunteers were
instructed to avoid any other drugs, including alcohol,
caffeine or nicotine for two weeks before and during the
course of the study.
On study day 1, all subjects received, in a fasting
state (at least 10 hours fasting), a single 2 mg dose of
intravenous infusion of levosimendan, over 10 minutes.
Analysis of plasma samples for levosimendan,
OR1855 and OR1896 concentrations
Plasma concentrations of levosimendan, OR1855
and OR1896 were measured by using liquid chromatography tandem mass spectrometry at the Department
of Drug Analysis of Abbott Laboratories.
Pharmacokinetic variables
Values for the pharmacokinetic parameters of levosimendan, OR1855 and OR1896, including the maximum
observed plasma concentration (Cmax), the time to Cmax
(peak time, Tmax), the terminal phase elimination rate
constant (b), terminal phase elimination half-life (t1/2),
and the area under the plasma concentration-time curve
(AUC) from time 0 to the time of the last measurable
concentration (AUCt) and from time 0 to infinite time
(AUC¥), were determined using noncompartmental methods. Clearance (CL) and volume of distribution (Vd) for
levosimendan were determined using noncompartmental
methods. The WinNonlin version 5.0.1 of Pharsight
Corp. was used for PK parameters calculation.
In addition, plasma protein binding and redistribution phenomenon were also determined. The plasma
protein binding (Pb) was calculated using: Pb = (1 - Cf/Ct)
´ 100%, where Cf: concentration of the top layer after
centrifugation, and Ct: initial plasma concentration before centrifuge.
Blood samples for levosimendan, OR1855 and
OR1896 concentration assay
Blood samples (6 mL) from each patient were obtained from an antecubital vein in the contralateral arm
(the other was for infusion) for levosimendan; OR1855
and OR1896 concentration assay were drawn into precooled plastic tubes containing ethylenediaminetetraacetic acid (EDTA) as an anticoagulant. The blood samples were collected at -15 min, 0 min (end of infusion), 5
min, 10 min, 20 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12
hr, 24 hr, 32 hr, 48 hr, 60 hr, 72 hr, 120 hr, 168 hr and
240 hr following dosing.
Immediately after collection, the blood samples
were inverted several times to ensure good mixing of
the blood and anticoagulant. Blood samples were kept
in ice and the plasma was separated within 10 minutes
by centrifugation in a centrifuge for 10 minutes at
approximately 3300 rpm. At least 2 mL of plasma was
transferred into one pre-cooled polypropylene test tube.
The plasma samples were frozen immediately at -70 to
-80 °C until shipped to Abbott Laboratories.
Pharmacodynamic variables
Left atrium diameter (LA), left ventricle end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD),
heart rate (HR), pre-ejection period (PEP), LV ejection
time (LVET), systolic time interval (STI), mean circumferential fiber shortening (MVcf), ejection fraction (EF),
cardiac output (CO), cardiac index (CI), aortic valve peak
velocity (AOPV) and mitral valve peak velocity (MVPV)
were measured and calculated.
In vitro protein binding assay
Blood samples (6 mL for each and 12 mL in total) for
protein binding assay were collected at 0 min and 10
min after infusion stopped for each subject. The blood
samples were drawn into pre-cooled plastic tubes containing sodium heparin as an anticoagulant. The subActa Cardiol Sin 2014;30:298-307
Safety variables
The following safety evaluations were performed
during the study: adverse event monitoring and vital
signs, physical examination, electrocardiography (ECG)
and laboratory test assessments.
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Pharmacokinetics and Pharmacodynamics of Levosimendan
Study procedure
A complete medical history, including alcohol, tobacco and nicotine-containing product use histories was
taken when blood samples (6 mL for each and 12 mL in
total) for protein binding assay were collected at 0 min
and 10 min after infusion was stopped for each subject.
The medical history was updated on study day 1, and the
medical history obtained at screening served as the baseline for clinical assessment. Medication (prescription or
over-the-counter, including vitamins and herbal supplements) use from 4 weeks prior to study drug administration through the end of the study was also recorded. A
physical examination was performed at screening. A brief
physical examination was performed on the study day 1
(-60 min), day 3 (48 ± 0.5 hr), day 4 (72 ± 0.5 hr), day 6
(120 ± 0.5 hr), day 8 (168 ± 0.5 hr) and day 11 (240 ± 0.5
hr) or upon subject discontinuation. A symptom-directed
physical examination was performed when necessary.
The physical examination performed at screening served
as the baseline physical examination for clinical assessment. Any significant physical examination findings after
dosing were recorded as adverse events.
Patient body weight was measured at screening
(baseline for clinical assessment), -60 min on the study
day 1, and day 11 (240 ± 0.5hr) or upon subject discontinuation in the study.
Body temperature (oral), blood pressure and pulse
were measured at screening, on the study day 1 (-60
min, -10 min, 0 min, 5 min, 10 min, 20 min, 30 min, 1 hr,
2 hr, 4 hr, 6 hr, 8 hr, 12 ± 0.5 hr), day 2 (24 ± 0.5 hr, 32 ±
0.5 hr), day 3 (48 ± 0.5 hr, 60 ± 0.5 hr), day 4 (72 ± 0.5
hr), day 6 (120 ± 0.5 hr), day 8 (168 ± 0.5 hr), and day 11
(240 ± 0.5 hr) or upon early discontinuation.
Blood pressure and pulse rate were measured after
the subject had been lying down for at least 3 minutes.
The measurements were completed within 5 minutes
prior to draw of PK blood sample.
The vital signs measurements just prior to dosing on
study day 1 served as the baseline measurements for
clinical assessment.
A 12-lead resting ECG was obtained at screening, on
the study day 1 (-60 min, 10 min, 1 hr, and 6 hr), day 3
(48 ± 0.5 hr) and day 11 (240 ± 0.5 hr) or upon early discontinuation. The ECG measurements at -60 min on the
study day 1 served as the baseline measurements for
clinical assessment.
An appropriately qualified cardiologist at the study
site read all ECGs. The reader wrote on the ECG tracing
his/her global interpretation as either “normal ECG” or
“abnormal ECG” and then signs and dates the ECG. The
QT interval measurement (corrected by Fridericia formula, QTcF) was documented only if the reader selects
the “prolonged QT” box.
Echocardiography recording and analysis
Echocardiographic recordings were obtained on
study day 1 (-60 min, -10 min, 0 min, 5 min, 10 min, 20
min, 30 min, 1 hr, 2 hr, 4 hr, and 6 hr) or upon early discontinuation.
Cardiac function indices were evaluated by a Hewlett Packard SONOS ultrasound system with phasedarray Doppler (Model 5500). M-mode, two-dimensional
(2D) echocardiographic images and pulsed-wave Doppler velocity signals were recorded on computer hard disc
and magneto-optical (MO) disc for a later retrieval and
analysis. The subjects were examined in a slightly leftlateral decubitus position during quiet respiration. Left
parasternal long-axis, left parasternal short-axis, apical 4
chamber, apical 5-chamber views were recorded. Doppler tracings of aortic flow were obtained using the apical
5-chamber view, with the sample-volume placed just beyond the valve leaflets within the proximal aortic root.
Slight adjustments in transducer angulations or sample-volume position were at times required to maximize
the audio and graphic quality of the Doppler signal. The
aortic valve opening on parasternal long axis view, velocities of mitral and aortic flow were recorded over several cardiac cycles at a monitor sweep speed of 100
mm/sec. AOPV and MVPV were measured. M-mode
echocardiographic measurements followed the standard
method as recommended by the American Society of
Echocardiography.21 LVEDD and LVESD were measured in
parasternal long-axis view at the level between the papillary muscle and mitral leaflet tips. LA was measured at
the aortic valve level. Left ventricle volume (V) was determined by the diameter (D) using Teichholz’s equation: V = [7.0/(2.4 + D)] ´ D.22 Stroke volume (SV) equals
LVEDV-LVESV; EF equals SV/LVEDV, cardiac output equals
SV ´ HR, and CI equals SV ´ HR/body surface area. The
PEP was the time duration measured from the onset of
ventricular depolarization (onset of QRS complex on simultaneous electrocardiogram) to the opening of the
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Acta Cardiol Sin 2014;30:298-307
Kai-Min Chu et al.
aortic valve. LVET was measured from the opening to
the closure of the aortic valve. All measurements were
made with the on board computer. Systolic time interval
was calculated by the equation PEP/LVET.
Table 1. Pharmacokinetic parameters of levosimendan,
OR1855 and OR1896 of subjects after IV infusion of 2
mg of levosimendan
Ethnicity comparison
The pharmacokinetic and pharmacodynamic parameters were tested among study result and previous
Caucasian male results23 by analysis of variance (ANOVA)
for any ethnic difference. P < 0.05 was considered significant.
Cmax, ng/mL
Mean (SD)
Median
Tmax, hr
Mean (SD)
Median
b, 1/hr
Mean (SD)
Median
t1/2, hr
Mean (SD)
Median
AUCt, hr×ng/mL
Mean (SD)
Median
AUC¥, hr×ng/mL
Mean (SD)
Median
CL, L/hr
Mean (SD)
Median
Vd, L
Mean (SD)
Median
Pharmacokinetic
parameters
RESULTS
A total of 14 Chinese male subjects in the age range
of 25.0 ± 2.8 years old, weight of 66.8 ± 5.2 kg, and
height of 173.5 ± 3.5 cm had completed the study.
Assessment of pharmacokinetics
Table 1 shows the pharmacokinetic variables in this
study. Figure 1 shows the mean concentration-time
curve of levosimendan after intravenous infusion of 2
mg of levosimendan.
The pharmacokinetic parameters were calculated
using non-compartment model and actual time vs. concentration of levosimendan, OR1855 and OR1896. For
levosimendan, Cmax, Tmax, b, t1/2, AUCt, AUC¥, CL, and Vd
were 256.1 ± 37.8 ng/mL, 0.02 ± 0.06 hr, 0.60 ± 0.07
1/hr, 1.18 ± 0.18 hr, 206.6 ± 35.0 hr×ng/mL, 207.5 ± 35.2
hr×ng/mL, 9.89 ± 1.78 L/hr and 9.83 ± 1.41L, respectively.
For OR1855 and OR1896, there was not enough
concentration data to estimate the pharmacokinetic
parameters in most subjects. Pharmacokinetic parameters of OR1855 could be estimated for only one subject and OR1896 could be estimated for only two subjects. For these subjects only Cmax, Tmax and AUCt could
be estimated.
Levosimendan
(n = 14)
OR1855
(n = 1)
OR1896
(n = 2)
256.1 (37.8)
248.2
0.6 (-)
0.6
1.1 (0.01)
1.1
0.02 (0.06)
0
60 (-)
60
72 (0)
72
18.7 (-)
18.7
83.6 (0.2)
83.6
0.60 (0.07)
0.61
1.18 (0.18)
1.13
206.6 (35.0)
207.9
207.5 (35.2)
208.8
9.89 (1.78)
9.58
9.83 (1.41)
9.84
AUCt, area under the concentration versus time curve from
time 0 to t; AUC¥, area under the curve from time 0 to infinity;
CL, clearance; Cmax, peak concentration; Tmax, time to reach
peak concentration; t1/2, half-life; Vd, volume of distribution; b,
terminal elimination rate constant.
Plasma protein binding of levosimendan
The plasma protein binding of levosimendan was
99.15 ± 0.28%.
Assessment of pharmacodynamics
The pharmacodynamic parameters included systolic
Acta Cardiol Sin 2014;30:298-307
Figure 1. The mean ± SD of plasma concentration-time profile of
levosimendan of 14 subjects after IV infusion of 2 mg of levosimendan.
302
Pharmacokinetics and Pharmacodynamics of Levosimendan
and diastolic blood pressure, heart rate, and the following echocardiography parameters: LA, PEP, LVET, PEP/
LVET, HR, LVEDD, LVESD, EF, CO, CI, AOPV, MVPV, and
MVcf.
The changes in the pharmacodynamic parameters
versus time profile of subjects at different time points
before and after IV infusion of 2 mg of levosimendan are
shown in Figures 2-5. For most of the parameters, the
maximum hemodynamic effect was seen within 10 or 20
minutes after the end of infusion.
The Cmax, AUCt, and AUC¥ of levosimendan of Chinese subjects were significantly higher than in the Caucasian subjects. Mean ± SD of weight un-normalized and
normalized CL of levosimendan of Chinese and Caucasian subjects were 9.9 ± 1.8 vs. 17.4 ± 2.7 L/hr and
0.149 ± 0.025 vs. 0.246 ± 0.028 L/hr/kg. It was found
that CL of levosimendan of Chinese subjects were significantly lower than Caucasian subjects irrespective of
whether CL was normalized by weight or not.
The elimination half-life of levosimendan of Chinese
subjects was significantly longer than Caucasian subjects (1.18 ± 0.18 vs. 0.76 ± 0.10 hr).
The results suggest that Chinese subjects eliminated levosimendan significantly slower than Caucasian subjects leading to higher exposure of levosimendan in Chinese subjects as compared to Caucasian
subjects.
Comparisons of pharmacokinetic parameters
between Chinese and Caucasian subjects
Table 2 shows the comparisons of pharmacokinetic
parameters of levosimendan between Chinese and Caucasian subjects.
Figure 2. Mean ± SD of heart rate and blood pressure of subjects
before and after IV infusion of 2 mg of levosimendan. dBP, diastolic
blood pressure; HR, heart rate; sBP, systolic blood pressure.
Figure 4. Mean ± SD of cardiac output and cardiac index of subjects
before and after IV infusion of 2 mg of levosimendan. CL, clearance; CO,
cardiac output.
Figure 3. Mean ± SD of left atrium, left ventricle end-systolic and
end-diastolic dimensions and ejection fraction of subjects before and
after IV infusion of 2 mg of levosimendan. EF, ejection fraction; LA, left
atrium diameter; LVEDD, left ventricle end-dia-stolic diameter; LVESD, LV
end-systolic diameter.
Figure 5. Mean ± SD of aortic valve pulse velocity and mitral valve
pulse velocity of subjects before and after IV infusion of 2 mg of
levosimendan. AOPV, aortic valve peak velocity; MVPV, mitral valve
peak velocity.
303
Acta Cardiol Sin 2014;30:298-307
Kai-Min Chu et al.
Comparisons of pharmacodynamic parameters
between Chinese and Caucasian subjects
Table 3 shows the comparisons of pharmacodynamic parameters after IV infusion of 2 mg of levosimendan between Chinese and Caucasian subjects.
The percentage changes of pharmacodynamic parameters of Chinese subjects after IV infusion of 2 mg of
levosimendan were similar to those of Caucasian subjects except for EF. The EF increased up to 12.2 ± 11.4%
in Chinese subjects after the end of intravenous infusion, which was significantly lower than in Caucasian
subjects where EF increased up to 22.7 ± 7.0% (p =
0.0282).
Safety evaluation
Throughout the study period, 2 subjects were reported to have experienced 3 adverse events (chest
tightness, cough rhino rhea nasal stiffness and tachycardia). No subject experienced any serious adverse event
and no subject discontinued due to any adverse event.
In terms of these three reported adverse events, one
was probably not related to the study drug; the other
two, in the investigator’s opinion, were also not related
to the study drug.
Table 2. Comparisons of pharmacokinetic parameters between
Chinese and Caucasian subjects
Parameters
This study
(n = 14)
23
Orion report
(n = 8)
Dose & route
2 mg, IV infusion 2 mg, IV infusion
Protein binding (%)
99.16 ± 0.28
†
Weight (kg)
66.8 ± 5.2
77.9 ± 5.3
†
Height (cm)
173.5 ± 3.50
185.0 ± 3.4
†
Cmax (ng/mL)
256.1 ± 37.8
142.1 ± 17.5
†
Cmax/weight (ng/mL/kg)
03.874 ± 0.762 1.840 ± 0.309
†
AUCt (hr×ng/mL)
206.6 ± 35.0
114.0 ± 18.0
†
AUC¥ (hr×ng/mL)
207.5 ± 35.2
117.0 ± 17.0
†
AUC¥/weight (hr×ng/mL/kg) 03.138 ± 0.660 1.520 ± 0.300
†
CL (L/hr)
09.9 ± 1.8
17.4 ± 2.7
Vd (L)
09.8 ± 1.4
11.7 ± 1.9*
†
01.18 ± 0.18
00.76 ± 0.10
t1/2 (hr)
DISCUSSION
In our study subjects, plasma concentration of levosimendan was higher with lower clearance and longer
elimination half-life than in Caucasian subjects. However, the inotropic index, as EF, was less increased than
in Caucasian subjects. The higher protein binding in our
subjects might explain this. In our study, the percentage
of protein binding of plasma levosimendan is 99.15 ±
0.28%, higher than the previously reported 95-98%.10-12
When the fraction unbound is lower, less free drug is
distributed in to red blood cells and tissue, and also less
free drug is available for both renal excretion and
AUCt, area under the concentration versus time curve from
time 0 to t; AUC¥, area under the curve from time 0 to infinity;
CL, clearance; Cmax, peak concentration; t1/2, half-life; Vd,
volume of distribution; 23, Orion Pharmaceutica, Report No.
300101, 1993.
#
†
* p < 0.05; p < 0.01; p < 0.005.
Table 3. Comparisons of absolute values and (% change) of pharmacodynamic parameters 20 mins after IV infusion 2 mg of
levosimendan between Chinese and Caucasian subjects
Parameters
Dose & route
HR (beat/min)
sBP (mmHg)
dBP (mmHg)
LVESD (mm)
LVEDD (mm)
EF (%)
CO (L/min)
23
This study (n = 14)
Orion report (n = 8)
2 mg, IV infusion
00.75 ± 13 (+14.3 ± 11.2%)*
117 ± 12 (+7.0 ± 11.1%)
63 ± 6 (+0.9 ± 18.6%)
27 ± 4 (-13.3 ± 8.9%).
45 ± 3 (-4.4 ± 5.8%)0.
#
0070 ± 8 (+12.2 ± 11.4%)
004.8 ± 0.6 (+15.6 ± 18.0%)
2 mg, IV infusion
00058 ± 8 (+10.1 ± 14.2%)
115 ± 8 (+3.5 ± 7.0%)
00.48 ± 8 (-0.16 ± 11.0%)
0.33 ± 3 (-12.9 ± 3.2%)
.53 ± 4 (-0.8 ± 4.3%)
0067 ± 4 (+22.7 ± 7.0%)
00005.1 ± 0.3 (+32.2 ± 26.1%)
CO, cardiac output; dBP, diastolic blood pressure; EF, ejection fraction; HR, heart rate; sBP, systolic blood pressure; LVEDD, left
ventricle end diastolic dimension; LVESD, left ventricle end systolic dimension; IV, intravenous; 23, Orion Pharmaceutica, Report
No. 300101, 1993.
#
* Percent changes between -10 and 20 min after IV infusion were shown in brackets; p < 0.05 when % Change after IV infusion
comparison between Chinese and Caucasian subjects with ANOVA test.
Acta Cardiol Sin 2014;30:298-307
304
Pharmacokinetics and Pharmacodynamics of Levosimendan
displacement of drug from tissue to plasma, than the
higher plasma concentration means lower tissue concentration and thus will have smaller pharmacodynamic
effect. This effect has been demonstrated in digoxin, a
cardiac glycoside, which binds strongly to the myocardial tissue of the heart. If patients who are on digoxin
take a quinidine, steady-state digoxin plasma levels increase, possibly due to displacement of the tissuebound digoxin.33-35
Therefore, when applying our study result in determining the infusion rate and duration, subsequent studies based only on plasma concentration are probably
not appropriate. Careful monitoring of the therapeutic
effect is also important.
hepatic biotransformation, which might be demonstrated by a decreased clearance and a longer
half-life.24,25 Less tissue distribution might also indicate
less target organ distribution and less pharmacodynamic effect as shown by less increased EF. There are
important clinical considerations when using a drug
with very high (> 95%) protein binding rate.26 First of all,
the patient’s plasma protein concentration should be
considered. If a patient has a low plasma protein concentration, then for any given dose of drug the concentration of free bioactive drug might be higher than anticipated. A number of diseases such as cirrhosis of liver,
nephrotic syndrome, malnutrition, age, trauma, and related circumstances affect the plasma protein concentration. In nephrotic syndrome, excessive renal loss of
plasma protein and accumulation of waste metabolites
such as urea and uric acid, as well as an accumulation of
drug metabolites, may also alter protein binding of
drugs.27 Second, drug-drug and drug-metabolite interactions are also important in a high protein binding drug
with a narrow therapeutic index such as warfarin.28 In
this case one drug might displace a second bound drug
from the protein, causing a sudden increase in pharmacologic response due to an increase in free drug concentration. Third, the increase of plasma concentration of a
drug might not necessarily mean the increase of the
pharmacodynamic effect. In a condition with no change
of the protein binding, higher plasma concentration will
have higher free drug concentration and the following
greater pharmacodynamic effect according to the doseor concentration-response curve. However, displacement of drug from plasma protein or target tissue is
completely different.29 If a free drug is increased due to
drug-interaction with the displacement by a second
drug from the plasma protein-binding site, than the tissue distribution will be increased and the pharmacodynamic effect will be increased. The increased free
drug will also increase the elimination and total plasma
concentration will transiently be increased and returned
to the baseline level before drug-interaction. This has
been shown in the drug interaction with warfarin.28,30-32
If a free drug increases due to low plasma protein with
less binding site, the change in pharmacodynamic effect
will be the same as in the condition of displacement
from plasma protein binding site. On the other hand, if a
drug-interaction acts at the tissue-binding site with
CONCLUSIONS
The administration of intravenous levosimendan
into healthy Chinese volunteers was safe, well-tolerated
and had a significant inotropic effect. The clearance of
levosimendan from Chinese subjects was significantly
lower, and the elimination of half-life longer than in
Caucasian subjects.
ACKNOWLEDGMENTS
Authors thank Abbott Pharmaceuticals for supporting this study, providing the raw data of previously unpublished studies and plasma sample analysis. The protocol was initiated by Abbott Pharmaceuticals and revised by authors. The conduction, pharmacokinetic analysis and manuscript preparation were not supported.
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