Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis

Prospective, open-label clinical trial

N= 8

To characterize the pharmacokinetics of ranolazine in patients undergoing hemodialysis

500 mg (n= 3)

1000 mg (n= 5)

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

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

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.

65 hours post-dose observation period

Primary: Pharmacokinetic parameters of ranolazine

Secondary: Hemodialysis reduction ratio

1000 mg (n= 5)

Male, n

3

Age, years

Weight, kg

Hemoglobin, g/dL

Albumin, g/dL

QTc Interval, msec

Parameter

Maximum concentration, mcg/mL

Time to maximum concentration, hr

Elimination phase apparent half-life, hr

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

Apparent volume of distribution, L/kg

Apparent off-hemodialysis clearance, L/hr/kg

Percent dialysis reduction ratio

*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.

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

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.

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.

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

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

Female

White

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)

Severe vs. healthy

AUC_0-12, 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) 

C_max, 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) 

AUC_0-12, C_max, t_1⁄2, and C_trough for the ranolazine metabolites CVT-2512 and CVT-2738 were significantly increased in subjects with severe renal impairment versus healthy subjects (p< 0.05)

AUC_0-12, C_max, and C_trough 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. 

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)

Age, years

Female

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

0.012

Control vs. nicorandil: 0.023

Control vs. ranolazine: 0.012

AKI

0.044

Control vs. nicorandil: 0.093

Control vs. ranolazine: 0.171

Change in SCr from baseline

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

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. 

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

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

Exclusion Criteria

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

Outcome Measures

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

Male

White

Weight, kg

Body mass index, median

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

Hospitalization for HF

Recurrent ischemia

Ischemic ST-segment depression on cECG

Adverse Events

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