Abstract
Background and Objective
In patients with impaired renal function, the pharmacokinetics of a drug may be altered, resulting in decreased renal excretion or metabolism, and altered absorption, plasma protein binding or distribution. Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder. Vilazodone is extensively hepatically metabolized with minimal renal excretion. The primary objective of this study was to assess the pharmacokinetics of a single 20-mg dose of vilazodone in subjects with mild or moderate renal impairment.
Methods
This was a Phase 1, open-label, single-dose study of vilazodone in community-dwelling subjects with renal impairment and in healthy subjects to evaluate the pharmacokinetics of vilazodone in the presence of renal impairment. Thirty-two subjects were enrolled: eight subjects with mild (estimated glomerular filtration rate [est GFR] >50–80 mL/min) renal impairment matched individually by age, sex and body mass index to eight control subjects with normal renal function (est GFR >80 mL/min), and eight subjects with moderate (est GFR ≥30–50 mL/min) renal impairment matched with eight control subjects with normal renal function. Subjects received a single, 20-mg dose of vilazodone and pharmacokinetics, safety and plasma protein binding were assessed for 14 days. The pharmacokinetic parameters calculated were maximum plasma concentration (Cmax), time to maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time zero to 24 h, AUC from time zero to the last measurable concentration, AUC from time zero to infinity estimated by linear trapezoidal rule and extrapolation, oral clearance, terminal elimination rate constant, elimination half-life (t½), free fraction in plasma, apparent free drug clearance, amount of vilazodone recovered in urine 0–96 h following drug administration, percent of dose recovered in urine over 96 h following drug administration, renal clearance and volume of distribution. Safety assessments were adverse events, clinical laboratory test results, 12-lead electrocardiograms and vital signs.
Results
Vilazodone pharmacokinetic parameters in renally impaired subjects were variable but not substantially different from healthy controls. Mean values for vilazodone Cmax and AUC were similar among groups. Mean t½ (35.7 and 34.8 h mild and moderate vs. 37.0 and 34.8 h matched controls), total drug clearance (19.9 and 25.1 L/h vs. 26.4 and 26.9 L/h), and mean vilazodone recovery in urine (1.21 % and 0.58 % vs. 0.95 % and 0.81 %) were similar for mild and moderate renally impaired subjects and matched controls with normal renal function. There were no apparent systematic trends in vilazodone pharmacokinetic parameters associated with decreasing renal function. Protein binding was variable (coefficient of variation, 29–65 %) but not substantially different among the three groups, and total drug clearance was not affected. Safety and tolerability of vilazodone were comparable in all groups of subjects.
Conclusion
This study suggests that systemic exposure of vilazodone is not affected by mild or moderate renal impairment. No dose adjustments are recommended in patients with mild or moderate renal impairment.
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Acknowledgements
This study was funded by PGxHealth LLC, a subsidiary of Clinical Data, Inc. (acquired by Forest Laboratories, Inc.). PGxHealth LLC was involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Editorial assistance was provided by Prescott Medical Communications and was funded by Forest Laboratories, Inc.
Ramesh Boinpally and John Edwards are employees of Forest Research Institute. James Longstreth and Marijke Adams were paid consulting fees by Forest Laboratories, Inc. Harry Alcorn has no financial disclosures relevant to this study.
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Boinpally, R., Alcorn, H., Adams, M.H. et al. Pharmacokinetics of Vilazodone in Patients with Mild or Moderate Renal Impairment. Clin Drug Investig 33, 199–206 (2013). https://doi.org/10.1007/s40261-013-0061-5
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DOI: https://doi.org/10.1007/s40261-013-0061-5