Effects of renal impairment on multiple-dose pharmacokinetics of extended-release ranolazine
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Design
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Phase 1, open-label study
N= 29
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Objective
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To investigate the effect of renal impairment on the steady-state pharmacokinetics (PK) of ranolazine and 3 major metabolites after multiple oral dosing
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Study Groups
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Healthy (n= 8)
Renal impairment (n= 21)
Mild (n= 7)
Moderate (n= 7)
Severe (n= 7)
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Inclusion Criteria
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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
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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
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Methods
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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.
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Duration
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Trial: January 2001 to June 2001
Intervention: 3 days
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Outcome Measures
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PK parameters for ranolazine and metabolites (CVT-2514, CVT-2512, CVT-2738)
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Baseline Characteristics
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All subjects (N= 29)
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Age, years
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57.3 ± 11.3 |
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Female
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8 (27.6%) |
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White
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29 (100%) |
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Creatinine clearance, mL/min
Healthy
Mild
Moderate
Severe
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96.9 ± 13.7 (n= 8)
63.4 ± 5.7 (n= 7)
39.4 ± 7.2 (n= 7)
20.4 ± 9.7 (n= 7)
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Results
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Endpoint
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Comparisons of renal impairment (geometric mean ratios at steady state)
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Mild vs. healthy |
Moderate vs. healthy |
Severe vs. healthy
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AUC0-12, ng/h/mL
Ranolazine
CVT-2514
CVT-2512
CVT-2738
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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)
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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)
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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)
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Cmax, ng/mL
Ranolazine
CVT-2514
CVT-2512
CVT-2738
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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)
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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)
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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)
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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).
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Adverse Events
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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.
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Serious Adverse Events: None reported
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Percentage that Discontinued due to Adverse Events: None reported
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Study Author Conclusions
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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.
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InpharmD Researcher Critique
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As this is a predominantly a PK analysis, full clinical implications of dosing in renally impaired patients may not be generalized from this study.
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