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PHARMACOKINETICS/SPECIAL POPULATIONS |
From Orion Pharma, Clinical R&D, Kuopio, Finland (Mr Puttonen), Espoo, Finland (Mr Kantele, Dr Kivikko), and Nottingham, UK (Dr Ruck); Orion Pharma, Nonclinical R&D, Espoo, Finland (Ms Ramela, Dr Häkkinen); and Helsinki University Central Hospital, Department of Medicine, Helsinki, Finland (Dr Pentikäinen). J. Puttonen's current address is Quintiles OY, Espoo, Finland.
Address for correspondence: Jaakko Puttonen, Quintiles OY, Metsänneidonkuja 10, 02130 Espoo, Finland; e-mail: jaakko.puttonen{at}quintiles.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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), with a mean (±SEM) t of 0.9 ± 0.0 hours in healthy subjects and 0.8 ± 0.1 hours in hepatically impaired subjects, respectively (not significant). The t of OR-1855 was 61 ± 5 hours in healthy subjects and 82 ± 3 hours (P < .01) in subjects with hepatic impairment. The t of OR-1896 was 62 ± 5 hours and 91 ± 5 hours (P < .01), respectively. However, the AUCs of OR-1855 and OR-1896 were similar in healthy volunteers and hepatically impaired subjects. The effect of acetylator status was seen as higher Cmax and AUC of OR-1855 in slow acetylators. Correspondingly, higher Cmax and AUC of OR-1896 were observed in rapid acetylators. Levosimendan was well tolerated in both study groups. In conclusion, the pharmacokinetics of the parent drug levosimendan was unaltered in subjects with moderate hepatic impairment, whereas the elimination of the metabolites was prolonged. However, because the maximum duration of levosimendan infusion is 24 hours, dosing adjustments of levosimendan may not be required in subjects with impaired hepatic function.
Key Words: Levosimendan • pharmacokinetics • OR-1896 • hepatic impairment
Intravenously administered levosimendan is eliminated rapidly, the half-life of the parent drug being approximately 1 hour both in healthy volunteers and in patients with heart failure. Total plasma clearance of levosimendan is about 220 to 300 mL/min (2.6-3.8 ml/min/kg), being 30% to 40% of liver plasma flow. Levosimendan is distributed to a small volume (apparent volume of distribution, Vz = 0.4l/kg after 24-hour infusion), and about 97% to 98% of the drug is bound to plasma proteins, mainly albumin.8-11
Levosimendan is extensively metabolized in the liver. The main metabolites of levosimendan are conjugates of the glutathione pathway, cyclic or N-acetylated cysteine or cysteinylglycine conjugates.12 The cyclic metabolites are predominantly found in the urine, whereas the N-acetylated conjugates are found in the feces. Levosimendan reaches the intestine by biliary excretion and diffusion through the intestinal wall. After intravenous administration, about 5% of the levosimendan dose is reduced in the intestine by bacteria to OR-1855, which is absorbed and further acetylated to metabolite OR-1896 (pharmacologically active).12 Acetylation is catalyzed by N-acetyltransferase, NAT2. This enzyme is polymorphically distributed in the population; about 40% to 70% of Caucasians are slow acetylators, whereas in Asian populations, only 10% to 30% are slow acetylators.13
The circulating metabolites OR-1855 and OR-1896 are formed and eliminated slowly after intravenous administration of levosimendan.10-12 Peak concentrations of OR-1855 and OR-1896 in plasma are observed 1 to 4 days after stopping the infusion. The half-life of the circulating metabolite OR-1896 is approximately 60 hours in healthy volunteers and 70 to 80 hours in patients with heart failure.10,11 Because this metabolite has a similar pharmacological activity to levosimendan,14-16 the longer half-life of the metabolite rather than that of the parent drug most likely explains the long-lasting effects of levosimendan.11
The pharmacokinetics of the parent drug is similar in rapid and slow acetylators, but the plasma levels of the metabolites OR-1855 and OR-1896 are dependent on the acetylator status of the study subject in patients with heart failure and in healthy volunteers. Plasma levels of the active metabolite OR-1896 have been up to 3.5 times higher in those determined as rapid acetylators compared with those with a slow acetylation status. However, the hemodynamic effects have been shown to be similar in both acetylator groups.11,12
Hepatic function plays a central role in drug metabolism. It affects on the disposition of drugs that are metabolized in the liver.17 Also, the synthesis of plasma proteins can be decreased in hepatic failure, causing reduction in the protein binding of a drug. Because many patients with congestive heart failure may have impaired hepatic function, it is important to know the effects of hepatic failure on the pharmacokinetics of levosimendan and its metabolites. This could help to refine the dosing of levosimendan in these patients.
In this study, the aim was to investigate the pharmacokinetics of levosimendan and its metabolites OR-1855 and OR-1896 in subjects with hepatic impairment and in healthy subjects. In addition, the purpose was to study the effect of acetylator status on the pharmacokinetics, to evaluate protein binding, and to assess safety and tolerability of levosimendan and the metabolites.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Levosimendan was given as an intravenous infusion of 0.1 µg/kg/min for 24 hours. Medical history was recorded, physical examination was performed, and laboratory tests were taken by a physician before the study at the screening visit and 13 days after stopping the levosimendan infusion. The physician checked the clinical condition of the subject during the follow-up visits. Safety of the subjects was evaluated by clinical monitoring by repetitive laboratory tests, electrocardiograms (ECGs), and blood pressure and heart rate recordings. Active inquiry and observation of individual subject was used to record any adverse events during the study.
Blood samples (5 mL) were taken into precooled polyethylene EDTA tubes for determination of the concentrations of levosimendan and its metabolites OR-1855 and OR-1896 in plasma. Samples were taken before levosimendan administration (predose sample) and at 2, 4, 8, 12, and 24 hours after the start of the infusion. Postinfusion samples were taken 30 minutes and 1, 2, 4, 12, 24, 36, and 48 hours after stopping the infusion. Blood samples were also taken on days 5, 7, 9, 11, and 14 after the start of the levosimendan infusion. The blood samples taken during the infusion period were taken from the arm opposite to that of the infusion.
For the determination of protein binding of levosimendan and its metabolites OR-1855 and OR-1896, blood samples (10 mL) were taken into precooled polyethylene EDTA tubes at 24 hours and 48 hours after the start of the infusion. The protein binding of levosimendan, OR-1855, and OR-1896 in plasma was determined using an ultracentrifugation technique. The plasma samples were ultracentrifuged, after which the concentration of levosimendan, OR-1855, and OR-1896 in the ultracentrifugation supernatant was determined by liquid chromatography tandem mass spectrometry. The free fraction of levosimendan, OR-1855, and OR-1896 in plasma was calculated by comparing the analyte concentrations in the supernatant with the analyte concentrations in the corresponding pharmacokinetic plasma sample.
Bioanalytical Methods
The bioanalytical assay was validated over a concentration range of 0.200 to 50.0 ng/mL for levosimendan and 0.500 to 50.0 ng/mL for OR-1855 and OR-1896. The quality control samples were assayed at 0.6, 15, and 40 ng/mL for levosimendan and at 1.5, 15, and 40 ng/mL for OR-1855 and OR-1896. Accuracy (indicated by percent bias), based on the theoretical concentration of quality control samples at 3 concentrations across the calibration range, varied from 3.9% to 7.6%, from -6.2% to -2.7%, and from -4.2% to -1.4% for levosimendan, OR-1855, and OR-1896, respectively. Precision, expressed as the percent coefficient of variation (%CV) for quality control samples assayed, was 3.8% to 5.6% for levosimendan, 3.4% to 5.7% for OR-1855, and 5.7% to 7.0% for OR-1896. A Chromolith RP-18e reversed-phase column (100 x 4.6 mm ID, E. Merck, Darmstadt, Germany) was used with a Chromolith RP-18e precolumn (5 x 4.6 mm ID, E. Merck). The mobile phase consisted of 2 mM ammonium acetate (pH 6.0) and methanol-acetonitrile (80:20 v/v) in a mixture of buffer and organic of 62:38 v/v. The flow rate was 1.0 mL/min.
The column effluent was directed to a PE Sciex API 2000 triple quadrupole mass spectrometer (Perkin-Elmer Sciex Instruments, Foster City, California) equipped with a standard atmospheric pressure chemical ionization source. The mass spectrometer was set to monitor the reactions of m/z 279 
227 for levosimendan and m/z 282 230 for its internal standard (2H3)OR-1259, m/z 204 159 for OR-1855 and m/z 207 162 for its internal standard (2H3)OR-1539, and m/z 246 204 for OR-1896 and m/z 260 218 for its internal standard OR-1974. The N-acetyltransferase 2 (NAT2) genotype of the study subjects was determined using a polymerase chain reaction assay.19
Pharmacokinetic Analyses
Pharmacokinetic parameters were determined by noncompartmental methods using WinNonlin 4.0 Professional software (Pharsight Co, Cary, North Carolina). Elimination half-life (t), peak plasma concentration (Cmax), time to reach peak plasma concentration (tmax), total clearance (Cltot), volume of distribution at steady state (Vss), and area under the curve (AUC0-
) were determined for levosimendan. The same parameters, except Cltot, were determined for the metabolites OR-1855 and OR-1896.20
CLtot of levosimendan was determined as a ratio of administered dose to the area under the plasma concentration versus time curve:
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(h·ng/mL) is the area under the concentration-time curve extrapolated to infinity. Clearance was expressed as corrected to body weight (ie, l/h/kg). The protein binding of levosimendan, OR-1855, and OR-1896 was determined by calculating the unbound fraction (fu) in plasma:
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Statistical Evaluation
The pharmacokinetic parameters of levosimendan and its metabolites OR-1855 and OR-1896 were summarized using descriptive statistics for both study group and acetylation status.
Statistical evaluation of the pharmacokinetic parameters was performed using analysis of variance (ANOVA) methods using the SAS for Windows 8.0 software program (SAS, Cary, North Carolina). The statistical model included the study group as the fixed effects, the matched subject number nested within the study group, and the residual error term as the random effects. The AUC0- and Cmax values for both levosimendan and its metabolites OR-1855 and OR-1896 were log-transformed for the analysis; t, tmax, Cltot, and Vss for levosimendan and the t for the metabolites were analyzed untransformed. Continuous variables were summarized using means and standard error of means.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The most common concomitant treatments were loop diuretics and spironolactone. Two healthy subjects were on thyroxine substitution for hypothyreosis. They were euthyreotic during the study.
Pharmacokinetics
Levosimendan
No statistically significant differences (ns) in the pharmacokinetic parameters between healthy subjects and subjects with impaired hepatic function were found (see Table III). The elimination half-life of levosimendan was similar in subjects with hepatic impairment (0.8 ± 0.1 hours) and healthy subjects (0.9 ± 0.0 hours). The peak concentration (mean ± SEM) of levosimendan in healthy subjects was 31 ± 2 ng/mL and 39 ± 5 ng/mL in subjects with impaired hepatic function (ns) (Figure 1). The free unbound (fu) fraction of levosimendan in plasma was similar (ns) in both study groups (see Table VII).
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When study subjects were classified by group and acetylation status, statistically significant differences (P < .05) were observed in the t and Cmax of levosimendan between subjects with hepatic impairment and healthy subjects (see Table IV). There was 1 subject with rapid acetylator status in the hepatic impairment group whose pharmacokinetics differed clearly from that of other study subjects. This difference is illustrated with the large deviation in each pharmacokinetic parameter (see Table IV). It should also be noted that there were only 3 subjects in that group, hampering the reliability of the finding.
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OR-1855
Maximum concentrations of OR-1855 in plasma were achieved 2 to 3 days after the start of the study drug infusion in both groups (see Figure 2). Elimination of OR-1855 was significantly slower (P < .01) in subjects with impaired hepatic function compared with healthy subjects with a t of 82 ± 11 and 61 ± 18 hours, respectively.
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) and Cmax of OR-1855 were greater in slow acetylators compared with rapid acetylators in both study subject groups, but the difference was not statistically significant (see Figures 4-5, Table V).
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The elimination half-life of OR-1855 in the slow acetylators was statistically significantly longer in subjects with impaired hepatic function than in healthy subjects (P < .01). A similar finding was observed in rapid acetylators, but the difference was not statistically significant.
OR-1896
Peak concentrations of OR-1896 in plasma were achieved 2 to 3 days after starting the infusion irrespective of the subject's physiological status and genotype (see Figures 3 and 6). However, Cmax was significantly lower (P < .05) and t longer (P < .01) in subjects with impaired hepatic function compared with healthy subjects (see Figure 3, Tables III and VI). The difference in t between the slow acetylators was significant (P < .01). The trend was similar also between rapid acetylators, but this was not statistically significant. Plasma levels of OR-1896 were lower in subjects with impaired hepatic function compared with healthy study subjects. Subjects with slow acetylator status in the hepatic impairment group had numerically, but not statistically significant, lower plasma OR-1896 concentrations compared with the corresponding group in healthy subjects. Rapid acetylators in the hepatic impairment group had significantly (P < .05) lower OR-1896 concentrations in plasma compared with the corresponding group in healthy subjects (see Figure 6). In addition, the AUC of OR-1896 both in slow and rapid acetylators in subjects with hepatic impairment was significantly lower (P < .05) than in corresponding healthy groups.
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Protein Binding
The mean unbound fraction (fu) of levosimendan in plasma was similar (ns) in healthy subjects and in subjects with impaired hepatic function (see Table VII).
The mean unbound fraction of OR-1855 and OR-1896 in healthy subjects was 64% ± 6% and 70% ± 6%, respectively. Correspondingly, in subjects with hepatic impairment, the unbound fraction of OR-1855 and OR-1896 was 63% ± 8% and 64% ± 8% (see Table VII). There were no statistically significant differences (ns) in protein binding between the study groups. The number of subjects varied due to insufficient data available for the determination of protein binding (concentrations below the quantitation limit).
Safety
All subjects completed the 24-hour infusion period, and there were no permanent discontinuations of levosimendan infusion in either subject group. A total of 31 adverse events (AEs) by 16 subjects were reported during the study, 8 in each study group. All AEs were mild to moderate in severity, the most frequent being headache (6 events in healthy subjects and 5 in subjects with hepatic impairment) and dizziness (1 event in both study groups).
The changes in safety laboratory variables were of minor clinical importance. Mean blood hemoglobin decreased by 1.1 g/L and 7.5 g/L in healthy subjects and in subjects with hepatic impairment, respectively. Mean serum potassium decreased by 0.3 mmol/L and 0.2 mmol/l in the respective study groups. Mean heart rate was elevated in both study groups from 2 hours after the start of the study drug infusion and was at its maximum on day 3 (increase of 13.0 bpm in healthy subjects and 7.6 bpm in subjects with hepatic impairment). The effect on heart rate was maintained until day 9 in both groups. There was a small decrease in mean blood pressure from baseline in both study groups during the 24-hour infusion with levosimendan. This decrease was most pronounced at 12 hours (-17 mmHg in healthy subjects and -11 mmHg in subjects with hepatic impairment) and was still present on day 2 in both study subject groups.
Acetylation status had no clinically significant effect on the safety variables measured in either study group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Impaired hepatic function, including cirrhosis, may be present in patients with heart failure. In addition, chronic heart failure is associated with decreased blood flow to the main drug-metabolizing organs (ie, the liver and kidneys). This may reduce the volume of distribution and impair the clearance of a drug.21 The effect of hepatic impairment on the pharmacokinetics of levosimendan is important to understand to guide the dosing of levosimendan in these patients. Renal function in the subjects with hepatic impairment in our study was normal, and they did not have heart failure. A group of 12 healthy volunteers matched with age, sex, and weight served as a control group.
The main metabolic pathway of levosimendan in vivo is via glutathione conjugation. About 5% of the levosimendan dose is reduced in the intestine by bacteria to OR-1855, which is absorbed and further acetylated to an active metabolite OR-1896 by the N-acetyltransferase enzyme. The glutathione pathway is very extensive in the liver but has also been found in extrahepatic tissues (eg, in intestine and kidneys).22 However, there are only few experimental observations in man about the glutathione conjugation activity in hepatic impairment.23 As the pharmacokinetics of levosimendan were not altered in moderate hepatic impairment, the conjugation reaction seems to be preserved in moderate hepatic cirrhosis. Conjugation reactions are in general believed to be more resistant than phase I reactions (eg, oxidation and reduction) in liver patients.22 This may provide an explanation for there being no difference in the pharmacokinetics of levosimendan between the 2 study groups.
The pharmacokinetic properties of levosimendan were similar to those obtained previously from studies in which a continuous 24-hour infusion of levosimendan was administered.11,12 Levosimendan was eliminated rapidly from the plasma after stopping the infusion, whereas the metabolites OR-1855 and OR-1896 were formed and eliminated more slowly. The elimination half-life of both OR-1855 and OR-1896 was approximately 1.5 times longer, whereas the peak concentrations of the metabolites were lower in subjects with hepatic impairment than in healthy subjects.
The acetylator status of the subjects was determined, but the number of subjects in each group was small, and affirmative conclusions on the differences between rapid and slow acetylators cannot be drawn. In accordance with the earlier data,12 the pharmacokinetics of levosimendan itself was independent of the acetylator status. However, there were statistical differences in elimination half-life and peak concentration in plasma, but these were modest from a clinical point of view and are most likely explained by the small number of subjects in the different acetylator groups.
Exposure of OR-1896 was greater in rapid acetylators and that of OR-1855 higher in slow acetylators (higher Cmax and AUC), which has also been seen in previous studies with intravenous levosimendan. The acetylator status seemed to have similar effects on the pharmacokinetics of the metabolites both in healthy subjects and in subjects with hepatic impairment.
The binding of levosimendan to plasma proteins was high (approximately 98% bound) and that of the metabolites considerably lower (30%-37% bound) in both study groups, which is in accordance with previous studies.10,12 N-acetyltransferase activity did not affect the protein binding of levosimendan or its metabolites.
The dose of levosimendan (0.1 µg/kg/min for 24 hours) used in the present study is approximately half of the maximally recommended dose in patients with heart failure. The dose was well tolerated in both study subject groups, with all subjects enrolled in the study completing the 24-hour infusion.
The overall safety profile of levosimendan in both study groups was similar to that observed in previous studies.24 Adverse events were reported with a similar rate in both study subject groups. Consistent with previous trials, headache and dizziness were the most frequently recorded adverse events in both subject groups and are most likely associated with the vasodilatory effect of levosimendan and OR-1896. Increases in heart rate and decreases in blood pressure were observed in both study subject groups. Similar hemodynamic changes observed in this study have been seen in earlier levosimendan studies. The prolonged increase in heart rate was seen in both groups up to day 9, which is most likely explained by the prolonged pharmacological activity of OR-1896.
The present study indicates that the pharmacokinetics of the parent compound is not affected by hepatic impairment. Although we studied only subjects with moderate hepatic impairment, it is likely that these findings are true also in mild hepatic impairment. The overall elimination of the levosimendan metabolites OR-1855 and OR-1896 was slightly prolonged in subjects with hepatic impairment, and one cannot rule out that further prolongation in subjects with severe hepatic impairment would take place. Because levosimendan is administered as a single infusion for up to 24 hours and its AUC and Cmax were not altered, the consequences of slight prolongation of the elimination of the metabolites should not have major clinical implications. This assumption is further supported by the hemodynamic responses and the safety profiles that were similar in healthy subjects and in subjects with impaired hepatic function.
In conclusion, the pharmacokinetics of levosimendan is not affected by moderate hepatic impairment, but the elimination of the levosimendan metabolites is slightly prolonged. The hemodynamic and safety responses were similar in both treatment groups. Because the recommended infusion of levosimendan is maximally 24 hours, dose adjustments in subjects with a moderate degree of hepatic impairment may not be necessary.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Mr Puttonen, Mr Kantele, Dr Kivikko, Dr Ruck, Ms Ramela, and Dr Häkkinen are employees of Orion Pharma. Dr Pentikäinen owns a minor amount of Orion Pharma stocks.
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REFERENCES |
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