What is the half-life of Ranolazine?

Ranolazine Half-Life

The half-life of ranolazine in the extended-release formulation is approximately 7 hours, while the immediate-release formulation has a shorter half-life of 1.4-1.9 hours. 1

Pharmacokinetic Properties of Ranolazine

Ranolazine demonstrates distinct pharmacokinetic characteristics that are important for clinical use:

• Absorption and Distribution:

  • Peak plasma concentrations are reached between 2-5 hours after oral administration of the extended-release formulation 2
  • Protein binding is approximately 61-64% over the therapeutic concentration range 1
  • Volume of distribution at steady state ranges from 85 to 180 L 1
  • Food has no important effect on the maximum concentration (Cmax) or area under the curve (AUC) of ranolazine, allowing it to be taken without regard to meals 2

• Metabolism:

  • Extensively metabolized in the gut and liver 2
  • Primary metabolism occurs via CYP3A enzymes and to a lesser extent by CYP2D6 2
  • Less than 5% is excreted unchanged in urine and feces 2
  • Exhibits flip-flop kinetics with the extended-release formulation, where the rate of absorption becomes the rate-limiting step in elimination 1

• Elimination:

  • After a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces 2
  • Oral plasma clearance diminishes with dose from an average of 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily 1

Clinical Implications of Ranolazine's Half-Life

The 7-hour half-life of the extended-release formulation allows for twice-daily dosing, which has several important clinical implications:

• Dosing Schedule:

  • Initial dose is 500 mg orally twice daily 3
  • Can be uptitrated to a maximum dose of 1000 mg orally twice daily if needed 3
  • Steady state is generally achieved within 3 days of twice-daily dosing 2

• Pharmacokinetic Linearity:

  • At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC increase slightly more than proportionally to dose (2.2- and 2.4-fold, respectively) 2
  • With twice-daily dosing, the trough:peak ratio of ranolazine plasma concentration is 0.3 to 0.6 2

Special Population Considerations

The half-life and pharmacokinetics of ranolazine may be affected in certain patient populations:

• Hepatic Impairment:

  • Ranolazine is contraindicated in patients with liver cirrhosis due to potential accumulation 3
  • In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc prolongation is much steeper 2

• Renal Impairment:

  • Area under the curve (AUC) increases up to 2-fold with advancing degrees of renal impairment 1
  • Dose adjustment may be necessary in patients with significant renal dysfunction 3

• Drug Interactions:

  • Strong CYP3A inhibitors like ketoconazole can increase plasma levels of ranolazine by 220% 2
  • Moderate CYP3A inhibitors like diltiazem and verapamil can increase plasma levels by 50-130% 2
  • CYP3A inducers like rifampin can decrease plasma concentrations by approximately 95% 2

The extended half-life of ranolazine contributes to its efficacy in managing chronic stable angina while allowing for a convenient twice-daily dosing regimen that promotes medication adherence.