Influence of chronic kidney disease and haemodialysis treatment on pharmacokinetics of nebivolol enantiomers

Abstract

Aim: The present study evaluated the pharmacodynamics and pharmacokinetics of nebivolol enantiomers in patients with chronic kidney disease (CKD) and in patients undergoing haemodialysis.

Methods: Forty-three adult patients were distributed into three groups: healthy volunteers and hypertensive patients with normal kidney function (n = 22); patients with stage 3 and 4 CKD (n = 11); and patients with stage 5 CKD undergoing haemodialysis (n = 10). The subjects received a single oral dose of 10 mg racemic nebivolol. Serial blood samples were collected up to 48 h after administration of the drug and heart rate variation was measured over the same interval during the isometric handgrip test. The nebivolol enantiomers in plasma were analysed by liquid chromatography-tandem mass spectrometry.

Results: The pharmacokinetics of nebivolol is enantioselective, with a greater plasma proportion of l-nebivolol. CKD increased the area under the concentration-time curve (AUC) of l-nebivolol (6.83 ng.h ml(-1) vs. 9.94 ng.h ml(-1) ) and d-nebivolol (4.15 ng.h ml(-1) vs. 7.30 ng.h ml(-1) ) when compared with the control group. However, the AUC values of l-nebivolol (6.41 ng.h ml(-1) ) and d-nebivolol (4.95 ng.h ml(-1) ) did not differ between the haemodialysis and control groups. The administration of a single dose of 10 mg nebivolol did not alter the heart rate variation induced by isometric exercise in the investigated patients.

Conclusions: Stage 3 and 4 CKD increases the plasma concentrations of both nebivolol enantiomers, while haemodialysis restores the pharmacokinetic parameters to values similar to those observed in the control group. No significant difference in heart rate variation induced by isometric exercise was observed between the investigated groups after the administration of a single oral dose of 10 mg nebivolol.

Keywords: CYP2D6; chronic kidney disease; nebivolol; pharmacokinetics; phenotype.

Figure 1

Plasma concentration vs. time curves of the nebivolol enantiomers in patients in the control (n = 22), chronic kidney disease (CKD) (n = 11) and haemodialysis (n = 10) groups treated with a single oral dose of 10 mg racemic nebivolol. Values are expressed as the mean ± standard error of the mean

Figure 2

Box plot comparing pharmacokinetic parameters (C _max, AUC and oral clearance) of the l‐nebivolol and d‐nebivolol enantiomers between the control and CKD groups and between the control and haemodialysis groups. AUC, area under the concentration–time curve; CKD, chronic kidney disease; C _max, maximal plasma concentration

Figure 3

Pharmacokinetic–pharmacodynamic analysis (inhibitory E _max model) of the d‐nebivolol isomer as a function of heart rate variation induced by isometric handgrip exercise in all patients classified as extensive metabolizers of cytochrome P450 2D6 (n = 43), E _max, maximum heart rate variation