Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis

Bridget A Scoville, Jonathan H Segal, Noha N Salama, Michael Heung, Barry E Bleske, Rachel F Eyler, Bruce A Mueller, Bridget A Scoville, Jonathan H Segal, Noha N Salama, Michael Heung, Barry E Bleske, Rachel F Eyler, Bruce A Mueller

Abstract

Purpose: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis.

Methods: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier NCT01435174 at Clinicaltrials.gov). Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters.

Results: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%.

Conclusions: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population.

Keywords: Ranolazine; end stage renal disease; hemodialysis; pharmacokinetics.

Figures

Figure 1.
Figure 1.
Ranolazine plasma concentration-time profiles in patients receiving either 500 mg (Subjects 1–3) or 1000 mg (Subjects 4–8) doses. HD designates the period during which hemodialysis occurred.
Figure 2.
Figure 2.
Plasma concentration-time profiles for the three major metabolites of ranolazine in patients receiving a 500 mg oral dose of ranolazine. Data is presented as mean ± standard deviation. HD designates the period during which hemodialysis occurred.
Figure 3.
Figure 3.
Plasma concentration-time profiles for the three major metabolites of ranolazine receiving a 1000 mg oral dose of ranolazine. Data is presented as mean ± standard deviation. HD designates the period during which hemodialysis occurred.

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Source: PubMed

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