title: Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-release tablets.
abstract: 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 (AUC0-12) by 76% (P < .001) and maximum plasma concentration C(max) by 51% (P < .01). The AUC0-12 ratio (metabolite/ranolazine) decreased for all metabolites in parallel with the degree of hepatic impairment. AUC0-infinity for the CYP3A substrate midazolam administered as a single dose was significantly correlated with ranolazine AUC0-12 at steady state (r2 = .33, P < .001). Over the time interval studied, ranolazine was well tolerated in healthy subjects and hepatically impaired subjects.
authors.affiliation: Clinical Pharmacology, CV Therapeutics, Inc, Palo Alto, California, USA.
authors.forename: Hisham
authors.initials: H
authors.lastname: Abdallah
authors.forename: Markus
authors.initials: M
authors.lastname: Jerling
mesh_terms: D000083:Acetanilides; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D000069458:Ranolazine; D013607:Tablets
chemical_list: D000083:Acetanilides; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D010879:Piperazines; D013607:Tablets; D003577:Cytochrome P-450 Enzyme System; D000069458:Ranolazine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam