Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-release tablets

The effect of hepatic impairment on the pharmacokinetics of a sustained-release formulation of ranolazine and 3 major metabolites was investigated in an open-label, parallel-group study. Ranolazine (875-mg loading dose followed by 500 mg every 12 hours for a total of 4 maintenance doses) was administered to subjects with mild (n = 8) or moderate (n = 8) hepatic impairment and a matched control group of healthy volunteers (n = 16). Moderate, but not mild, hepatic impairment significantly increased ranolazine steady-state area under the concentration-time curve (AUC(0-12)) by 76% (P <.001) and maximum plasma concentration C-max by 51% (P <.01). The AUC(0-12) ratio (metabolite/ranolazine) decreased for all metabolites in parallel with the degree of hepatic impairment. AUC(0-infinity) for the CYP3A substrate midozolam administered as a single dose was significantly correlated with ranolazine AUC(0-12) at steady state (r(2) =.33, P <.001). Over the time interval studied, ranolazine was well tolerated in healthy subjects and hepatically impaired subjects.