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Clinical Pharmacokinetics of Ranolazine

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Abstract

Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, β-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy.

Following administration of an oral solution or IR capsule, peak plasma concentrations (Cmax) are observed within 1 hour. After administration of radio-labelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61–64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180L.

Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4–1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500mg twice daily to 33 L/h at 1000mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state Cmax and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment.

Ranolazine is a weak inhibitor of CYP3A, and increases AUC and Cmax for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40–60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by C YP3 A inhibitors ranging from 1.5-fold for diltiazem 180mg once daily to 3.9-fold for ketoconazole 200mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

Funding to assist in the preparation of this review was provided by CV Therapeutics, Inc., Palo Alto, CA, USA

Dr Jerling was an employee of CV Therapeutics at the time of studies conduct and reporting, and is currently a consultant to CV Therapeutics.

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  1. Clinical Pharmacology, CV Therapeutics, Inc., Palo Alto, California, USA

    Markus Jerling

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Jerling, M. Clinical Pharmacokinetics of Ranolazine. Clin Pharmacokinet 45, 469–491 (2006). https://doi.org/10.2165/00003088-200645050-00003

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