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Pharmacodynamics and Pharmacokinetics of Oral Levosimendan and Its Metabolites in Patients With Severe Congestive Heart Failure: A Dosing Interval Study

From Cardiovascular Projects, Research Centre, Orion Pharma, Espoo, Finland (Dr Põder, Dr Sundberg, Dr Antila, S Rantanen); Mustamäe Hospital, Tallinn, Estonia (Dr Eha, Dr Heinpalu, Dr Loogna, Dr Planken); and Department of Clinical Pharmacology, Helsinki University Central Hospital, Finland (Dr Lehtonen).

Address for reprints: Pentti Põder, MD, Cardiovascular Projects, Research Centre, Orion Pharma, PO Box 65, Fin-02101 Espoo, Finland.

	ABSTRACT

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The objective of this study was to explore the pharmacodynamics and pharmacokinetics of oral levosimendan in patients with severe congestive heart failure. This was a randomized, parallel-group, double-blind, placebo-controlled trial. Oral levosimendan 2 to 8 mg daily or placebo was administered to 25 patients with New York Heart Association class III-IV congestive heart failure for 4 weeks. Pharmacodynamic variables consisted of heart rate-corrected electromechanical systole, heart rate, and systolic and diastolic blood pressure. The pharmacokinetics of levosimendan and its metabolites, OR-1855 and OR-1896, was assessed. The 4- to 8-mg daily doses of oral levosimendan showed moderate inotropic effects. Blood pressure remained unchanged with all doses. A moderate increase in heart rate was observed except with the 2-mg dose. Pharmacokinetic parameters of the metabolites increased linearly with the dose (P .002 for C_max and AUC_0-8h for both treatment groups). It was concluded that oral levosimendan has inotropic and chronotropic effects in patients with severe congestive heart failure. Plasma concentrations of its metabolites increase dose dependently.

Key Words: Levosimendan • OR-1855 • OR-1896 • pharmacokinetics • pharmacodynamics • congestive heart failure (CHF)

Levosimendan has an elimination half-life of about 1 hour. It has 2 circulating metabolites, the reduction metabolite OR-1855 and its acetylated form, OR-1896. The metabolites have half-lives of 70 to 80 hours.⁹ During intravenous administration of levosimendan, the metabolite levels increase slowly, and their maximum concentrations are seen about 2 days after withdrawal of a 24-hour infusion.¹⁰ The metabolite OR-1896 has hemodynamic properties similar to those of the parent drug.^11,12

Previous studies have shown that single oral doses of levosimendan have similar hemodynamic effects as the intravenous drug in patients with severe congestive heart failure.¹³ However, it is probable that during chronic administration, the metabolites contribute more extensively to the pharmacodynamic effects of the drug.

The present trial was designed to study the pharmacodynamics and pharmacokinetics of different doses of oral levosimendan. This is the first double-blind study in which the pharmacodynamics and pharmacokinetics of the metabolites were assessed after oral administration of levosimendan in patients with congestive heart failure.

	PATIENTS AND METHODS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Design
The study was a randomized, parallel-group, double-blind, and placebo-controlled phase II study. Each patient received an ascending dose of study medications on 2 consecutive periods for 2 weeks without a wash-out (Figure 1). Patients were randomized to 3 groups according to the method for sequential treatment design as follows:

View larger version (11K): [in this window] [in a new window]   Figure 1. Study flowchart.

Group I (low-dose group) received levosimendan 2 mg x 1 for 2 weeks and then 2 mg x 3 for an additional 2 weeks.

Group II (high-dose group) received levosimendan 2 mg x 2 for 2 weeks and then 2 mg x 4 for an additional 2 weeks.

Group III (placebo group) received placebo during both study periods.

The study was conducted according to the Declaration of Helsinki of the World Medical Association and its amendments. The study protocol was approved by the Ethics Committee of Tartu University. Written informed consent was obtained from all patients.

The timing of the assessments is depicted in Figure 2. The following baseline assessments were made: heart rate-corrected electromechanical systole (QS2i), heart rate (HR), systolic and diastolic blood pressure (sBP and dBP), and 6-minute walk test. A safety laboratory analysis was taken, and a 12-lead electrocardiography (ECG) recording and a 24-hour ambulatory ECG (Holter) were performed on the day prior to starting the study medication. At the end of the first medication period (day 14), the patients received their first drug dose of the day, and a 24-hour ambulatory ECG recording was started. The QS2i, HR, and sBP and dBP recordings were taken at -20 minutes (baseline) and at 2, 4, and 8 hours. A 6-minute walk test was performed 2 hours immediately after QS2i, HR, and sBP and dBP recordings. Venous blood samples for the determination of levosimendan concentration were drawn at -20 minutes and at 2, 4, and 8 hours. Metabolite concentrations were determined from the samples taken at -20 minutes, 2 hours, and 8 hours. A safety laboratory analysis was made, and a 12-lead ECG recording was performed at 8 hours. The next day, the patients started the second medication period. The same schedule was repeated at the end of the second treatment period (day 28).

View larger version (7K): [in this window] [in a new window]   Figure 2. Schedule of assessments on the last day of a 14-day treatment period.

One week after the last medication day of the second treatment period (day 35), the patients returned to the hospital for blood samples for metabolite determinations and for safety laboratory analysis and ECG (Figure 2).

Eligibility and Randomization
Patients with New York Heart Association (NYHA) class III-IV congestive heart failure were eligible. Other inclusion criteria were as follows: age 18 to 75 years, weight 50 to 100 kg, body mass index (BMI) < 32, medically stable condition for at least 5 days prior to study entry, walking distance 350 m in a 6-minute walk test, and echocardiographically measured left ventricular ejection fraction (LVEF) 35%.

Exclusion criteria comprised supine sBP < 90 or > 180 mmHg, acute myocardial infarction (AMI) within last 3 months prior to study entry, previous clinical evidence of sustained ventricular tachycardia, frequent nonsustained ventricular tachycardia or rapid supraventricular tachycardia within 4 weeks prior to study entry, resting HR < 55 or > 120 bpm, second- or third-degree atrioventricular (AV) block (patients with properly functioning pacemaker were eligible), clinically relevant renal (serum creatinine > 200 µmol/L) or hepatic failure, hemodynamically significant valvular disease, and participation in another clinical trial within 4 weeks prior to study entry.

A medical examination, including medical history and clinical examinations, was performed within 4 weeks before inclusion in the study. The safety laboratory parameters were determined, and the 24-hour ambulatory electrocardiography (Holter) and 6-minute walk tests were performed. The LVEF was determined by 2-dimensional echocardiography (Simpson rule).

Eligible patients were randomly assigned to receive oral levosimendan (Orion Pharma, Espoo, Finland) or matching placebo. The patients continued with their current treatment for heart failure during the study.

Pharmacodynamic Measurements
The pharmacodynamic variables consisted of QS2i, HR, sBP, dBP, and the 6-minute walk test at 2 hours after intake of the first capsule of the study drug on the last day of the treatment period. A 2-hour time point was prespecified in the study protocol because the maximum concentration of levosimendan was expected at that time point.

QS2i
For the determination of QS2i, ECGs and phonocardiograms were recorded simultaneously (Schiller CS-100, Schiller AG, Switzerland). Electromechanical systole (QS2) was measured from the beginning of the Q-wave in the ECG to the beginning of the aortic component of second heart sound in the phonocardiogram (A II). In the recordings in which no Q-wave was distinguishable, the beginning of the R-wave was used instead. For every patient, either the Q- or R-wave was consistently used in analyzing the tracings from all time points. Recordings were made at a paper speed of 100 mm/sec. Five to 10 cardiac cycles were averaged using a digitizer (Bitpad; Summagraphics, Fairfield, Conn). The QS2 was corrected for HR according to the formula QS2i = QS2 + 2.1 x HR.¹⁴ The digitizing of QS2 was performed by a person who was independent from the study team.

Blood Pressure, Heart Rate, and 24-Hour Ambulatory ECG (Holter)
Systolic and diastolic blood pressure (mmHg) were measured from the same arm in a supine position by an automatic oscillometric device (Omron M4, model HEM-722C; Omron Matsusaka Co, Japan). The HR (beats/min) was measured from ECG recordings. A 10-minute rest in the supine position preceded the measurements. Ambulatory ECG was recorded and analyzed using Holter Recorder Marquette (Series 8500; Marquette Electronics Inc, Milwaukee, Wis).

Six-Minute Walk Test
The walk test was carried out as follows: the patient walked for 6 minutes at his or her own pace from end to end in a corridor of 30 m. The patients were not encouraged during the test, and they were allowed to take pauses if symptoms so required. The walked distance was measured to the nearest 5 m.

Pharmacokinetics
The concentrations of levosimendan in plasma were determined by an automated sample preparation technique with reversed-phase high-performance liquid chromatography with UV detection.¹⁵ The concentrations of levosimendan metabolites, OR-1855 and OR-1896 in plasma, were determined by liquid chromatography/tandem mass spectrometry using the selected reaction monitoring technique. Individual plasma concentration-time data of levosimendan were analyzed using a standard noncompartmental method in the WinNonlin® Professional computer program (Version 3.1; Pharsight Corp, Mountain View, Calif).

Peak plasma concentration (C_max) and time to peak plasma concentration (t_max) of levosimendan were obtained straight from the plasma concentration-time data. The area under the plasma concentration-time curve was calculated from intake of the first capsule of the day to the last detectable concentration using the linear trapezoidal method (AUC_last).

The pharmacokinetics of levosimendan metabolites was analyzed on the last day in both study periods. Both C_max and AUC_8h were calculated for OR-1855 and OR-1896 using the standard noncompartmental method.

Assessment of Safety
The safety of the drug was followed during the study by laboratory tests, 12-lead ECG, Holter monitoring, and blood pressure and heart rate recordings. The adverse event inquiry was made at every visit. Patients were also encouraged to report spontaneously about their sensations and symptoms during the study.

Statistics
In hypothesis testing, the 2-sided level of 5% was considered the level of statistical significance. In the statistical analysis, the baseline values before the first medication period were used.

The change in QS2i, sBP, dBP, HR, and 6-minute walk test from baseline to 2 hours on the last treatment day of the study period was compared between 3 treatment groups in the 2 study periods separately using analysis of variance (ANOVA) with effect for treatment.

Descriptive statistics was applied for the pharmacokinetic parameters. The relationship between levosimendan dose and metabolite concentrations was tested using the paired t test. Also, the relationship between the pharmacokinetic parameters of levosimendan and its metabolites and daily dose was examined by using linear regression analyses.

Safety laboratory parameters were evaluated using descriptive statistics. Changes in ECG parameters were compared between the 3 treatment groups in the 2 study periods separately, using 1 sample t test, as well as ANOVA methods and changes in Holter parameters using the Cochran-Mantel-Haenszel test.

	RESULTS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Demographics
Baseline characteristics are presented in detail in Table I. The patient population consisted of 25 patients with a mean age of 58 years. Mean weight was 76 kg, height was 171 cm, and mean BMI was 26. Mean LVEF was 30%, and 6-minute walking distance was 289 m. Among the 25 patients, 2 were women. The etiology of CHF was coronary heart disease in 21 patients.

Pharmacodynamics
The pharmacodynamic results are presented in detail in Table II.

QS2i
QS2i shortened by 6 milliseconds in the low-dose group and by 23 milliseconds in the high-dose group at day 14 compared with the baseline. In the placebo group, QS2i shortened by 8 milliseconds. At day 28, the shortening of QS2i compared with the baseline was 11 milliseconds in the low-dose group and 28 milliseconds in the high-dose group. In the placebo group, QS2i shortened by 2 milliseconds. There was a significant difference in the change in QS2i between treatment groups (P = .016), which is attributable to the difference between the high-dose group and the placebo group at day 28 (P = .005). The effect of levosimendan on day 28 at 8 hours was similar to that seen at 2 hours (low-dose group: 526 ± 3 milliseconds; high-dose group: 498 ± 7 milliseconds, P = .003 in comparison with placebo [mean ± SEM are given]).

Heart Rate
In the low-dose and placebo groups, HR did not change, but in the high-dose group, it increased by 8 bpm in comparison to the baseline at day 14. By day 28, HR increased by 10 bpm in the low-dose group, by 8 bpm in the high-dose group, and by 5 bpm in the placebo group. There was no significant difference between the treatment groups regarding change in heart rate.

Blood Pressure
Systolic BP decreased by 2 mmHg in the low-dose group and by 5 mmHg in the placebo group. In the high-dose group, sBP increased by 5 mmHg by day 14. By day 28, sBP decreased by 5 mmHg in the placebo group, whereas in the levosimendan groups, it remained virtually unchanged.

Diastolic BP decreased by 6 mmHg in the low-dose group and by 2 mmHg in the high-dose group. In the placebo group, dBP increased by 6 mmHg compared with the baseline. There was no difference between treatment groups at day 14. Also, by day 28, dBP remained virtually unchanged in both levosimendan groups, whereas it increased in the placebo group compared with the baseline.

Six-Minute Walk Test
The 6-minute walk distance did not change significantly compared with the baseline in any of the groups, even though the improvement was highest in the high-dose levosimendan group.

Pharmacokinetics
The pharmacokinetics of levosimendan was determined on the last treatment day of each period. No differences were found in pharmacokinetic parameters of levosimendan between the medication periods in both treatment groups (Table III). The C_max and AUC_0-8h of both metabolites increased linearly with the dose (Table IV, Figure 3).

View larger version (17K): [in this window] [in a new window]   Figure 3. Levosimendan metabolites OR-1855 and OR-1896 plasma levels in different dose groups after 14 days of treatment.

Safety
Levosimendan was well tolerated. Only 2 patients experienced adverse events during the study. One patient, receiving 6 mg of levosimendan daily, experienced an episode of atrial fibrillation, which was detected from the ECG recording. The other patient, receiving 6 mg of levosimendan daily, discontinued the treatment due to sinus tachycardia and angina pectoris. This episode resolved, and no myocardial injury was detected.

No clinically significant changes were observed in safety laboratory parameters and in the incidence of arrhythmic events between treatment groups.

	DISCUSSION

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The patients in our study had NYHA class III and IV congestive heart failure and a low ejection fraction despite standard pharmacotherapy. Practically all patients received treatment with angiotensin-converting enzyme (ACE) inhibitors; more than two-thirds were treated with vasodilators, digoxin, and diuretics; and about one-third received beta-blockers. However, the patients were not decompensated like the patients enrolled in the studies with intravenous levosimendan.

The doses of levosimendan used in the present study have previously been shown to be effective in weaning inotrope-dependent patients from continuous intravenous therapy.¹⁶ In that study, the dose of levosimendan varied according to the individual hemodynamic response of the patient. In our study, a fixed dosing regimen was used to determine the levels of metabolites that can be expected during chronic administration of the oral drug. This regimen helped also to clarify the pharmacodynamic effects of the parent drug as well as the pharmacodynamic effects of different metabolite levels. One of the most important findings of the study was that the concentrations of metabolites increased linearly with the levosimendan dose. The pharmacokinetics of levosimendan was similar after the first dose of the last treatment day, showing that no cumulation of levosimendan occurred with any dosing interval.

In previous studies, QS2i has been shown to be a fairly specific and load-independent index of inotropy.¹⁷ Echocardiographic assessments could have given information on the effects of the drug on left ventricular volumes. However, combining systolic time intervals and echocardiography would have made the study difficult to carry out in practice. Furthermore, we have found QS2i to be a sensitive and well-reproducible measure of inotropy.^18,19 As the assessment of QS2i (and also other pharmacodynamic variables) was made at a 2-hour time point on the last day of each treatment period, the groups were equal with respect to the effect of levosimendan, so the differences between groups will show the effects of the active metabolite OR-1896. The effect of levosimendan regarding QS2i was similar at 8 hours (when there was no levosimendan in plasma), which also reflects the prolonged action of active metabolite OR-1896.

In our trial, levosimendan showed a moderate inotropic effect assessed by the shortening of QS2i. The inotropic effect was the smallest (similar to that seen with placebo) in the lowest dose group and largest in the highest dose group. However, the shortening of QS2i from the first treatment period to the second treatment period was only about 5 milliseconds in both treatment groups, despite the significant increase in metabolite levels. Furthermore, with the 4-mg daily dose, the shortening of QS2i was 23 milliseconds, but with the 6-mg daily dose, it was only 11 milliseconds compared with the baseline. At the same time, metabolite OR-1896 levels with the 4-mg and 6-mg daily doses were about 9 and 17 ng/mL, respectively. These observations may be related to the individual variability in the physiological response to the inotropic effect of metabolite OR-1896. In any case, a definitive dose response for the shortening of QS2i could not be established in our study.

A chronotropic effect (by 8-11 bpm) was observed with levosimendan doses of 4 to 8 mg. Only the lowest, the 2-mg daily dose, did not increase heart rate. In a previous study with the 2-mg single dose, no change in heart rate was also observed, which allows us to conclude that the metabolite levels after the 2-mg daily dose did not have chronotropic effects.²⁰ Interestingly, the same phenomenon, which was observed regarding QS2i, was seen in the high-dose group with respect to chronotropy, as no further increase in heart rate was seen when the daily dose was doubled.

No effect on blood pressure was seen with any levosimendan dose. In a previous study with the 2-mg single dose, the decrease in both systolic and diastolic blood pressure was about 4 mmHg.²⁰ It is important that blood pressure virtually did not change compared with the baseline during the whole 4-week treatment period in any treatment group. This shows that the vasodilatory effect of metabolites, if any, is very small. Surprisingly, no improvement in the 6-minute walk test was seen with levosimendan. It is possible that the treatment period was too short to achieve improvement in this variable or that a learning effect confounded the results because the improvement was seen also in the placebo group.

The present study was designed as a dose-ranging study for oral levosimendan. It does not yet clarify the most appropriate daily dose and dose interval for long-term use. Probably the most critical issue is the risk-benefit profile of the active metabolite OR-1896 because the effect of the metabolite will last substantially longer than the effect of the parent drug and will depend on the daily dose of levosimendan. On the other hand, the single dose of levosimendan in any multiple-dose regimen should also be well tolerated. Taking this into account, one can consider that the 1- to 2-times daily administration with approximately 2 mg as a single dose of levosimendan may be optimal for both an efficacy and a safety perspective. In our study, daily oral doses of 4 to 8 mg had inotropic effects; they did not cause arrhythmia despite chronotropic effects and were rather well tolerated. However, there are no good surrogates for the long-term effects of oral inotropic drugs because many drugs with initial favorable effects on hemodynamics and exercise tolerance had worsened the prognosis of the patients in the long term.^21-23 Therefore, studies with longer administration periods with careful dose titration, based on individual responses, are needed for characterizing the long-term outcome effects.

In conclusion, oral levosimendan 4 to 8 mg possessed moderate inotropic and chronotropic effects in patients with severe congestive heart failure. The formation of levosimendan metabolites is increased linearly with the daily dose.

	ACKNOWLEDGEMENTS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
We thank study nurse Mrs Olga Shantseva, Mr Harri Salonen, and Mrs Merja Sjöblom for technical assistance; Pekka Heikkilä, MSc, and Tarmo Laine, MSc, for statistical analyses; and Pekka Suhonen, PhD, and Prof Markku S Nieminen, MD, for commenting on the manuscript.

	FOOTNOTES

 
This study was supported by grant from Orion Pharma, Finland.

DOI: 10.1177/0091270004268319

Submitted for publication September 4, 2003; Revised version accepted June 17, 2004.

	REFERENCES

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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