Effect of renal impairment on multiple-dose pharmacokinetics of extended-release ranolazine

Abstract

Ranolazine is a novel compound under development as an antianginal agent. The multiple-dose pharmacokinetics of extended-release ranolazine and 3 major metabolites was investigated in healthy subjects (N = 8) and subjects with mild to severe renal impairment (N = 21). The ranolazine AUC0-12 (area under the concentration-time curve between 0 and 12 hours after dosing) geometric mean ratio versus healthy subjects at steady state was 1.72 (90% confidence interval [CI], 1.07-2.76) in subjects with mild impairment, 1.80 (90% CI, 1.13-2.89) in those with moderate impairment, and 1.97 (90% CI, 1.23-3.16) in those with severe renal impairment. Creatinine clearance was negatively correlated with AUC0-12 and the maximum observed concentration for ranolazine and the O-dearylated metabolite (P < .05 for all variables), as well as the N-dealkylated metabolite (P < .001), but not for the O-demethylated metabolite. Less than 7% of the administered dose was excreted unchanged in all groups, indicating that factors other than reduced glomerular filtration rate contributed to the increase in ranolazine concentrations in renal impairment. No serious adverse events were observed in the study. Copyright © 2005 by the American Society for Clinical Pharmacology and Therapeutics.