Abstract
Objective
To assess the differences in the pharmacokinetics and cardiac safety of ebastine and its active metabolite, carebastine, in patients with normal and impaired renal function.
Methods
Twenty-four patients with varying degrees of renal impairment (mild, moderate or severe: n = 8 per group) and 12 healthy subjects participated in an open-label, parallel-group, multicentre study. Ebastine 20mg was administered orally once daily for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours on day 1 and for 72 hours on day 5 by using a validated sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 ng/mL for ebastine and 1.00 ng/mL for carebastine. Renal function was assessed by measuring 24-hour creatinine clearance (CLCR) at baseline. Cardiac and general safety parameters were also monitored.
Results
The pharmacokinetics of ebastine were not modified by renal impairment. No correlation between ebastine pharmacokinetics and renal function, as expressed by CLCR assessed 2 days prior to dosing, was observed. Comparison of the plasma exposure and the elimination half-life of ebastine and carebastine between groups showed no significant differences. Therefore, no apparent accumulation of ebastine and carebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics for both healthy subjects and patients with renal impairment, even though the variability between the groups was large. In addition, no differences were observed in the safety of ebastine between patients with renal impairment and healthy subjects when assessing adverse events, vital signs, laboratory parameters or ECGs.
Conclusion
Ebastine was generally well tolerated in subjects with impaired renal function. No clinically important pharmacokinetic or safety differences were observed between patients with renal impairment and healthy subjects with normal renal function.
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Acknowledgements
This study was supported in part by a grant from Rhône-Poulenc Rorer (Collegeville, PA; now Sanofi-Aventis). Almirall Prodesfarma (Barcelona, Spain) is the originator of ebastine and is now responsible for its development. The clinical centres to which Robert Noveck, Richard Preston and Suzanne Swan are affiliated received grant research support from Rhône-Poulenc Rorer to conduct the investigation; however, no direct funds were paid to these authors.
Robert Noveck was the principal investigator in this study, and Rhône-Poulenc Rorer was primarily responsible for study protocol development and management, analysis and interpretation of the study data. The authors thank Almirall Prodesfarma for statistical review of this manuscript. The authors also wish to thank Michelle Tracy of Prous Science, who provided medical writing and editorial assistance on behalf of Almirall Prodesfarma.
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Noveck, R.J., Preston, R.A. & Swan, S.K. Pharmacokinetics and Safety of Ebastine in Healthy Subjects and Patients with Renal Impairment. Clin Pharmacokinet 46, 525–534 (2007). https://doi.org/10.2165/00003088-200746060-00006
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DOI: https://doi.org/10.2165/00003088-200746060-00006