The t(1/2) of the levosimendan metabolites was prolonged 1.5-fold and their AUC and C(max) were 2-fold in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.

Levosimendan is a vasodilator used in the treatment of acute heart failure. In the present study, the effect of hepatic impairment on the pharmacokinetics of levosimendan and its 2 metabolites, OR-1855 and OR-1896 (pharmacologically active), was investigated in 12 healthy subjects and 12 subjects with moderate hepatic impairment due to alcoholic cirrhosis of the liver but with no heart failure. In addition, the effect of acetylator status on the pharmacokinetics of levosimendan, OR-1855, and OR-1896 was evaluated. Safety and tolerability of levosimendan were also assessed. Levosimendan was given as an intravenous infusion of 0.1 microg/kg/min for 24 hours. Levosimendan showed similar C(max), AUC, and elimination half-life (t(1/2)), with a mean (+/-SEM) t(1/2) of 0.9 +/- 0.0 hours in healthy subjects and 0.8 +/- 0.1 hours in hepatically impaired subjects, respectively (not significant). The t(1/2) of OR-1855 was 61 +/- 5 hours in healthy subjects and 82 +/- 3 hours (P < .01) in subjects with hepatic impairment. The t(1/2) 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 C(max) and AUC of OR-1855 in slow acetylators. Correspondingly, higher C(max) 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.

Aims Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral L -dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of L -dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of L -dopa given as standard release L -dopa/carbidopa. Methods Six different doses of L -dopa/carbidopa were investigated in this placebocontrolled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups ( n = 14-16). Two different L -dopa/carbidopa doses were administered to each subject (50/ 12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/ 25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of L -dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(0,12 h) of L -dopa to a similar extent at all doses of L -dopa/carbidopa, that is by about 30-40% compared with placebo ( P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C max values for L -dopa at all L -dopa/ carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of L -dopa were maintained for a longer period at all doses of L -dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-Omethyldopa (3-OMD) to about 55-60% of the placebo treatment level ( P < 0.001, 95% CI -0.72, -0.35) and increased the mean AUC(0,12 h) of 3,4-dihydroxyphenylacetic acid (DOPAC) 2-2.6-fold compared with placebo ( P < 0.001, 95% CI 0.60, 1.10). The mean AUC(0,12 h) of 3-methoxy-4-hydroxy-phenylacetic acid (HVA) following entacapone was approximately 65-75% of that observed with placebo ( P < 0.001-0.05, 95% CI -0.76, -0.01) at each L -dopa/carbidopa dose except the 50/12.5 mg dose ( P > 0.05, 95% CI -0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC L -dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD ( P < 0.001, 95% CI -0.85, -0.68) and HVA ( P < 0.001, 95% CI -1.01, -0.18) in plasma at each L -dopa/carbidopa dose, whereas the AUC DOPAC/AUC L -dopa ratio was increased again at all doses ( P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did L -dopa/carbidopa affect the pharmacokinetics of entacapone.H. Heikkinen et al. 364

No abstract