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Pharmacokinetics of Aliskiren in Patients with End-Stage Renal Disease Undergoing Haemodialysis

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Abstract

Background and Objectives

Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis.

Methods

Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m2 high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations.

Results

Compared with the healthy subjects (1681 ± 1034 ng·h/mL), the area under the plasma concentration–time curve (AUC) from time zero to infinity was 61 % (haemodialysis at 48 h) and 41 % (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 ± 497 ng/mL in healthy subjects) was 17 % higher (haemodialysis at 48 h) and 16 % lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2 % of oral clearance and the mean fraction eliminated from circulation was 10 and 12 % in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred.

Conclusion

The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population.

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Acknowledgments

We thank Dr Kristin Lambert and Dr Ching-Ming Yeh from the Novartis Institutes for Biomedical Research for their support in study design and reviewing the statistical methods of the manuscript. This study was supported in part by an unrestricted grant from Novartis, Nuremberg, Germany. Diego Albrecht, Henk Johan Streefkerk and Sam Rebello are employees of Novartis and thus eligible for Novartis stock and stock options. Harm Peters and Torsten Slowinski have received funds for speaking at symposia organized on behalf of Novartis Pharma and Gambro, Germany. The other authors have no conflicts of interest to declare that are directly relevant to the content of this study.

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Correspondence to Harm Peters.

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Khadzhynov, D., Slowinski, T., Lieker, I. et al. Pharmacokinetics of Aliskiren in Patients with End-Stage Renal Disease Undergoing Haemodialysis. Clin Pharmacokinet 51, 661–669 (2012). https://doi.org/10.1007/s40262-012-0003-z

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