Is there any information about the use of Ranexa in renal failure patients and hemodialysis patients?

Comment by InpharmD Researcher

Limited clinical trials suggest that treatment with ranolazine in patients with renal failure or hemodialysis may be complicated, as the existing evidence suggests significant pharmacokinetic variability. Because ranolazine is largely cleared by the kidneys, renal dose adjustments will be necessary, but further studies are needed to determine treatment protocols and optimize therapy in this patient population.

Background

A 2015 general review briefly discusses the clearance of ranolazine regarding kidney function. Dose adjustments for ranolazine in chronic kidney disease (CKD) or dialysis patients are generally recommended, as 70% is cleared by the kidneys. However, the dose reduction strategies are not specified. [1]

References:

[1] Agrawal H, Aggarwal K, Littrell R, et al. Pharmacological and non pharmacological strategies in the management of coronary artery disease and chronic kidney disease. Curr Cardiol Rev. 2015;11(3):261-269. doi:10.2174/1573403x1103150514155757

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there any information about the use of Ranexa in renal failure patients and hemodialysis patients?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Tables 1-4 for your response.


Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis

Design

Prospective, open-label clinical trial

N= 8

Objective

To characterize the pharmacokinetics of ranolazine in patients undergoing hemodialysis

Study Groups

500 mg (n= 3)

1000 mg (n= 5)

Inclusion Criteria

Patients aged 18–74 with end-stage renal disease (ESRD) receiving maintenance hemodialysis for at least 3 months, weighing >40 kg, within 50–150% of ideal body weight, estimated glomerular filtration rate (eGFR) <10 mL/min, no infection, able to give informed consent

Exclusion Criteria

QTc interval >440 msec, hemoglobin <10 g/dL, plasma albumin <2.5 g/dL, liver disease (Child Pugh C or higher), hepatitis B, unstable blood pressure, need for >4 L fluid removal during hemodialysis, use of QT-prolonging drugs, major P-gp inhibitors, CYP3A4 inducers/inhibitors, pregnancy, breastfeeding, allergy to ranolazine, participation in another investigational drug study

Methods

Participants received a single dose of ranolazine (500 mg or 1000 mg). Blood samples were collected over 65 hours to determine pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine pharmacokinetic parameters.

Duration

65 hours post-dose observation period

Outcome Measures

Primary: Pharmacokinetic parameters of ranolazine

Secondary: Hemodialysis reduction ratio

Baseline Characteristics Characteristic 500 mg (n= 3)

1000 mg (n= 5)

Male, n

2 3
White, n 2

3

Age, years

32 (30–53) 33 (20–63)

Weight, kg

54 (48–68) 86 (55–93.5)

Hemoglobin, g/dL

12.2 (10.1–12.3) 10.7 (10.1–11.6)

Albumin, g/dL

4.7 (4.2–4.8) 4.1 (2.7–4.8)

QTc Interval, msec

429 (416–439) 455 (412–467)
Results

Parameter

500 mg (n= 3) 1000 mg (n= 4)*

Maximum concentration, mcg/mL

0.65 ± 0.27 1.18 ± 0.48

Time to maximum concentration, hr

8 ± 4 4.5 ± 2.5

Elimination phase apparent half-life, hr

3.6 ± 1.73 3.9 ± 0.55

Area under the curve (AUC) 0–18 hr, hr·mcg/mL

6.17 ± 3.2 10.33 ± 4.87

Apparent volume of distribution, L/kg

14.37 ± 3.2** 7.3 ± 1.5

Apparent off-hemodialysis clearance, L/hr/kg

0.66 ± 0.23** 1.34 ± 0.41

Percent dialysis reduction ratio

52.3 ± 8.1 69.2 ± 37.6%

*Excludes data from 1 participant who had inconsistent plasma ranolazine results.

**Excludes data from 1 participant who had ranolazine concentrations below the lower limit of quantification after 15 hours.

Adverse Events

No substantial changes in vital signs or QTc interval; one case of hyperkalemia unrelated to ranolazine.

Study Author 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.

Critique

This was deemed to be the first study to evaluate ranolazine pharmacokinetics in hemodialysis patients. However, its small sample size, limited sampling due to anemia risk, no mass balance or dialysate sample collection, and potential variability in CYP3A4 activity post-hemodialysis were not assessed.

References:

Scoville BA, Segal JH, Salama NN, et al. Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis. Ren Fail. 2019;41(1):118-125. doi:10.1080/0886022X.2019.1585371

 

Effects of renal impairment on multiple-dose pharmacokinetics of extended-release ranolazine

Design

Phase 1, open-label study

N= 29

Objective

To investigate the effect of renal impairment on the steady-state pharmacokinetics (PK) of ranolazine and 3 major metabolites after multiple oral dosing

Study Groups

Healthy (n= 8)

Renal impairment (n= 21)

Mild (n= 7)

Moderate (n= 7)

Severe (n= 7)

Inclusion Criteria

Age 18 to 75 years, body weight 40-120 kg, within 25% of ideal body weight, nonsmokers or light smokers able to abstain from smoking for 24 hours

Exclusion Criteria

Received another investigational drug within 12 weeks before start of the study (or within 4 weeks in case of renal impairment), had ongoing treatment with drugs causing significant inhibition of CYP3A or CYP2D6, had any surgical or medical condition that might interfere with the absorption, distribution, metabolism, or excretion of the drug, or were positive for human immunodeficiency virus or hepatitis B

Methods

Following an overnight fast, patients were given an initial loading dose of 875 mg ranolazine ER (500 mg + 375 mg tablets), followed by 500 mg ranolazine administered every 12 hours for a total of 4 maintenance doses. Treatment was discontinued after day 3.

Duration

Trial: January 2001 to June 2001

Intervention: 3 days

Outcome Measures

PK parameters for ranolazine and metabolites (CVT-2514, CVT-2512, CVT-2738)

Baseline Characteristics

 

All subjects (N= 29)

 

 

Age, years

57.3 ± 11.3    

Female

8 (27.6%)     

White

29 (100%)    

Creatinine clearance, mL/min

Healthy

Mild

Moderate

Severe

 

96.9 ± 13.7 (n= 8)

63.4 ± 5.7 (n= 7)

39.4 ± 7.2 (n= 7)

20.4 ± 9.7 (n= 7)

   

Results

Endpoint

Comparisons of renal impairment (geometric mean ratios at steady state)

Mild vs. healthy Moderate vs. healthy

Severe vs. healthy

AUC0-12, ng/h/mL

Ranolazine

CVT-2514

CVT-2512

CVT-2738

 

1.72 (1.07 to 2.76)

0.79 (0.38 to 1.62)

0.94 (0.47 to 1.89)

1.77 (1.14 to 2.76)

 

1.80 (1.13 to 2.89)

0.84 (0.41 to 1.71)

1.47 (0.73 to 2.96)

3.03 (1.95 to 4.73)

 

1.97 (1.23 to 3.16)

1.46 (0.71 to 3.00)

2.78 (1.38 to 5.60)

4.21 (2.70 to 6.55) 

Cmax, ng/mL

Ranolazine

CVT-2514

CVT-2512

CVT-2738

 

1.60 (1.05 to 2.43)

0.78 (0.37 to 1.62)

0.95 (0.48 to 1.88)

1.81 (1.15 to 2.85)

 

1.62 (1.06 to 2.45)

0.78 (0.37 to 1.62)

1.41 (0.71 to 2.80)

2.99 (1.90 to 4.69)

 

1.89 (1.24 to 2.87)

1.51 (0.72 to 3.16)

2.92 (1.47 to 5.80)

4.19 (2.67 to 6.59) 

AUC0-12, Cmax, t1⁄2, and Ctrough for the ranolazine metabolites CVT-2512 and CVT-2738 were significantly increased in subjects with severe renal impairment versus healthy subjects (p< 0.05)

AUC0-12, Cmax, and Ctrough for CVT-2738 were also significantly increased in patients with moderate renal impairment (p< 0.05).

The renal clearance for ranolazine and the 3 metabolites was significantly reduced in all renally impaired groups versus healthy subjects (p< 0.05).

Adverse Events

Common Adverse Events: The most frequently reported drug-related adverse events in renally impaired subjects included constipation (5/21 [23.8%]) and increased creatinine (5/21 [23.8%]). All adverse events were mild or moderate in severity. Adverse events were more frequently reported in patients with severe and moderate renal impairment compared to mild renal impairment (71.4% vs. 85.7% vs. 28.6%, respectively). No significant effect on supine systolic blood pressure and pulse were noted, however in patients with severe renal impairment, diastolic blood pressure was increased on day 3. 

Serious Adverse Events: None reported

Percentage that Discontinued due to Adverse Events: None reported

Study Author Conclusions

In conclusion, ranolazine pharmacokinetics is affected by renal function, with ranolazine AUC0-12 geometric mean ratio values versus those in healthy subjects at steady state of 1.72 (90% CI, 1.07-2.76) in subjects with mild impairment, 1.80 (90% CI, 1.13-2.89) in subjects with moderate impairment, and 1.97 (90% CI, 1.23-3.16) in subjects with severe renal impairment. Renal impairment is, therefore, a factor to consider when ranolazine doses are selected. Less than 7% of the administered dose was excreted unchanged in all groups, indicating that factors other than reduced glomerular filtration rate contributed to the increase in ranolazine concentrations in renal impairment. The exposure to the metabolite CVT-2738 increased more than proportionately to that of the ranolazine parent compound in subjects with impaired renal function, suggesting a significant direct renal excretion of this metabolite.

InpharmD Researcher Critique

As this is a predominantly a PK analysis, full clinical implications of dosing in renally impaired patients may not be generalized from this study. 



References:

Jerling M, Abdallah H. Effect of renal impairment on multiple-dose pharmacokinetics of extended-release ranolazine. Clin Pharmacol Ther. 2005;78(3):288-297. doi:10.1016/j.clpt.2005.05.004

 

Efficacy of nicorandil and ranolazine in prevention of contrast-induced nephropathy in patients with mild-to-moderate renal dysfunction: a randomized controlled trial

Design

Single-center, randomized controlled study

N= 315

Objective

To assess the efficacy of nicorandil and ranolazine in preventing contrast-induced nephropathy (CIN) in patients with mild-to-moderate renal dysfunction undergoing elective percutaneous coronary intervention (PCI)

Study Groups

Nicorandil (n= 105)

Ranolazine (n= 105)

Control (n= 105)

Inclusion Criteria

Age ≥ 18 years planned for elective PCI with estimated glomerular filtration rate (eGFR) between 30-89 mL/min/1.73 m2

Exclusion Criteria

Allergy to contrast agent, history of dialysis, NYHA IV heart failure, left ventricular ejection fraction (LVEF) < 30%, cardiogenic shock, malignancy, acute/chronic infection

Methods

Patients were randomized 1:1:1 to treatment with nicorandil, ranolazine, or control. Patients in nicorandil group received oral nicorandil 10 mg, TID 1 day before procedure and 2 days after PCI. Patients in ranolazine group received oral ranolazine 1,000 mg, BID 1 day before procedure and for 2 days after PCI. Patients in all groups, including control, received intravenous sodium chloride at a rate of 1.0 mL/kg/h (0.5 mL/kg/h if LVEF < 45%) from 6 hours before procedure to 12 hours after procedure. An iso-osmolar contrast agent (iodixanol) was used in all patients. 

Duration

Trial: July 2021 to December 2022

Intervention: 3 days

Outcome Measures

Primary: Incidence of CIN

Secondary: Incidence of acute kidney injury (AKI; rise in SCr ≥ 0.3 mg/dL within 48 hours of procedure)

Baseline Characteristics

 

Control (n= 105)

Nicorandil (n= 105)

Ranolazine (n= 105)  

Age, years

60.46 60.33  60.23   

Female

17.1% 12.4% 10.5%  

Comorbidities

Diabetes

Hypertension

 

39.0%

41.9%

 

35.2%

28.6%

 

40.0%

38.1%

 

Laboratory values

eGFR

Random blood sugar

Serum creatinine

Blood urea

Ejection fraction

 

60.26

148.92

1.323

39.64

46.57

 

63.64

148.48

1.268

37.15

45.48

 

63.16

153.30

1.286

37.39

45.29

 

Results

Endpoint

Control (n= 105)

Nicorandil (n= 105)

Ranolazine (n= 105)

p-Value

CIN

19 (18.1%) 8 (7.6%) 7 (6.6%)

0.012

Control vs. nicorandil: 0.023

Control vs. ranolazine: 0.012

AKI

15 (14.2%) 7 (6.6%) 8 (7.6%)

0.044

Control vs. nicorandil: 0.093

Control vs. ranolazine: 0.171

Change in SCr from baseline

0.078 -0.015 -0.005

0.018

Control vs. nicorandil: 0.030

Control vs. ranolazine: 0.060

Adverse events

All-cause mortality

Acute heart failure

End-stage kidney disease/RRT

Cardiac death

Myocardial infarction

Minor bleed

 

3 (2.86%)

2 (1.90%)

0

1 (0.95%)

2 (1.90%)

2 (1.90%)

 

2 (1.90%)

3 (2.86%)

0

1 (0.95%)

2 (1.90%)

2 (1.90%)

 

3 (2.86%)

3 (2.86%)

1 (0.95%)

2 (1.90%)

1 (0.95%)

3 (2.86%)

 

0.617

0.811

0.738

0.617

0.720

0.742

Adverse Events

See above

Study Author Conclusions

This randomized controlled study compared the protective effect of nicorandil plus hydration and ranolazine plus hydration to hydration alone in preventing CIN in patients with mild-to-moderate renal dysfunction undergoing elective PCI. The results favored a protective effect of nicorandil and ranolazine in preventing CIN. While this study adds to existing literature that supports a role for nicorandil in CIN prevention, the efficacy of ranolazine in protecting against CIN has been demonstrated in humans for the first time. As ranolazine is a remarkably well-tolerated drug, this pilot study paves the way for larger trials to assess the role of routine administration of this drug in patients at increased risk for developing CIN after PCI. 

InpharmD Researcher Critique

Generalizability of results is limited due to the single-center, non-blinded study design. Furthermore, the ranolazine arm of the study was planned as a pilot initiative and not as a noninferiority trial between ranolazine versus nicorandil, preventing an accurate statistical comparison. 



References:

Yusuf J, Prakash G, Safal S, Mehta V, Mukhopadhyay S. Efficacy of nicorandil and ranolazine in prevention of contrast-induced nephropathy in patients with mild-to-moderate renal dysfunction: a randomized controlled trial. Coron Artery Dis. 2024;35(3):186-192. doi:10.1097/MCA.0000000000001347

 

Clinical Features, Use of Evidence-Based Therapies, and Cardiovascular Outcomes Among Patients With Chronic Kidney Disease Following Non-ST-Elevation Acute Coronary Syndrome

Design

Multicenter, randomized, double-blinded, placebo-controlled trial

N= 6560

Objective

To evaluate the clinical features, use of evidence-based therapies, and cardiovascular outcomes among patients with chronic kidney disease following non–ST-elevation acute coronary syndrome

Study Groups

GFR ≥90 mL/min/1.73 m² (n= 1554)

GFR 60–<90 mL/min/1.73 m² (n= 3449)

GFR 30–<60 mL/min/1.73 m² (n= 1459)

GFR <30 mL/min/1.73 m² (n= 81)

Inclusion Criteria

Patients with at least 10 minutes of ischemic symptoms at rest and presented with non–ST-elevation ACS.

Exclusion Criteria

Persistent ST-elevation and hepatic disease.

Methods

Patients were randomized to ranolazine or placebo and categorized based on their glomerular filtration rate (GFR) estimated using the MDRD formula. Ranolazine dose was reduced to half in patients with severe renal insuffiicency.

Duration

Approximately 12 months follow-up.

Outcome Measures

Cardiovascular death or myocardial infarction, hospitalization for heart failure, recurrent ischemia, ischemic ST-segment depression on cECG

Baseline Characteristics

 

GFR ≥90 mL/min/1.73 m² (n= 1554)

GFR 60–<90 mL/min/1.73 m² (n= 3449)

GFR 30–<60 mL/min/1.73 m² (n= 1459)

GFR <30 mL/min/1.73 m² (n= 81)

 

Age, years

57 64 71 74  

Male

79.8% 66.5% 47.0% 48.1%  

White

93.9% 95.7% 95.2% 96.3%  

Weight, kg

83 81 78 78  

Body mass index, median

28 28 28 28  

Comorbidities

Diabetes mellitus

Hypertension

Hyperlipidemia

Current smoker

Prior myocardial infarction

Prior revascularization

Prior angina

Prior heart failure

 

31.5%

64.5%

64.3%

41.9%

30.1%

23.8%

48.2%

10.3%

 

30.6%

71.9%

67.0%

24.6%

33.0%

26.1%

53.9%

14.7%

 

42.6%

86.9%

72.1%

11.3%

40.8%

30.3%

66.5%

27.3%

 

59.3%

93.8%

76.0%

0.9%

39.5%

32.1%

55.7%

35.8%

 

Angiographic findings

0 vessel disease

1 vessel disease

2 vessel disease

3 vessel disease or left main

 

13.3%

31.6%

25.3%

29.9%

 

11.8%

29.1%

24.6%

34.5%

 

9.7%

20.0%

27.0%

43.4%

 

10.3%

15.4%

23.1%

51.3%

 

Results

Endpoint

GFR ≥90 mL/min/1.73 m² (n= 1554)

GFR 60–<90 mL/min/1.73 m² (n= 3449)

GFR 30–<60 mL/min/1.73 m² (n= 1459)

GFR <30 mL/min/1.73 m² (n= 81)

p-Value

CVD or MI

7.1% 8.8% 16.8% 28.7% < 0.001

Hospitalization for HF

2.0% 3.3% 8.6% 21.4% < 0.001

Recurrent ischemia

13.7% 14.7% 17.1% 15.3% 0.52

Ischemic ST-segment depression on cECG

17.2% 20.2% 23.9% 33.2% 0.79

Adverse Events

No significant treatment interaction for ranolazine vs placebo was observed in terms of adverse cardiovascular outcomes.

Study Author Conclusions

Patients with CKD had more cardiovascular risk factors and were less likely to receive evidence-based therapies. There was a strong, graded relationship between CKD severity and poor clinical outcomes, warranting efforts to optimize ACS treatment strategies in CKD patients.

InpharmD Researcher Critique

Limitations include a smaller number of patients with severe CKD and reliance on baseline creatinine for GFR estimation. The study was not designed to address the benefits and risks of invasive vs conservative treatment strategies in CKD patients.



References:

Rhee JW, Wiviott SD, Scirica BM, et al. Clinical features, use of evidence-based therapies, and cardiovascular outcomes among patients with chronic kidney disease following non-ST-elevation acute coronary syndrome. Clin Cardiol. 2014;37(6):350-356. doi:10.1002/clc.22253