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Effect of Hepatic Impairment on the Multiple-Dose Pharmacokinetics of Ranolazine Sustained-Release Tablets

From Clinical Pharmacology, CV Therapeutics, Inc, Palo Alto, California.

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- for the CYP3A substrate midazolam administered as a single dose was significantly correlated with ranolazine AUC_0-12 at steady state (r² = .33, P < .001). Over the time interval studied, ranolazine was well tolerated in healthy subjects and hepatically impaired subjects.

Key Words: Ranolazine • hepatic impairment • pharmacokinetics

Address for reprints: Markus Jerling, MD, PhD, Stavgardsgatan 30, Bromma 16756, Sweden.

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