# Presentation: 336491

## Clinical Evaluation of the Effects of Ranolazine on Ventricular Repolarization

**Andrew A. Wolff, MD, FACC**
**Sr VP, Clinical Research and Development**
**CV Therapeutics, Inc.**

## Effects of Ranolazine onCardiac Repolarization 

**The QTc effect of ranolazine is well characterized**
**At plasma concentrations up to 10,000 ng/mL**
**Including concentrations exceeding tolerability**
**Remains linear at 2.4 msec per 1000 ng/mL**
**2 to 5 msec over recommended dose range**
**Is ≤ 20 msec at the maximum recommended dose during maximal CYP3A4 inhibition**
**The cellular electrophysiology underlying the QTc effect of ranolazine is fundamentally different from that of drugs known to cause torsade de pointes**

## Ranolazine QTc Effects Extensively StudiedA Comprehensive Database

**25,497 QTc measurements in 2395 subjects/ patients on ranolazine**
**1714 subject/patient yr of observation**
**259 patients followed for ≥ 2 yr with ****serial ECGs**
**All ECGs in CVT-sponsored studies read by a central core ECG laboratory**
**Population QTc analysis of data from 15 studies**
**15,819 QTc-plasma concentration pairs**
**All observations at steady state**

## Assessment of QTc Effects of Ranolazine During Controlled Overdosing Ranolazine Infusion Study CVT 3111 Design 

**ECG**

**PK**

**Vitals**

**Ranolazine n = 22**
**Placebo n = 6**

**31 subjects: 16 male, 15 female**
**5137 ECGs (3355 on ranolazine)**

**0**

**5000**

**10000**

**15000**

**-24**

**0**

**24**

**48**

**72**

**96**

**120**

**Target [RAN], ng/mL**

**-24**

**0**

**24**

**48**

**72**

**96**

**120**

**-24**

**0**

**24**

**48**

**72**

**96**

**120**

**Ranolazine n = 22**
**Placebo n = 6**

**Ranolazine n = 7**
**Placebo n = 3**

**Time, hr**

**Placebo (single-blind, all subjects)**
**Ranolazine (double-blind)**

## Ranolazine Effect on ∆QTc During Controlled OverdosingInfusion to Intolerability in Study CVT 3111

**Ranolazine Effect on ∆QTc ****During Controlled Overdosing****Infusion to Intolerability in Study CVT 3111**

**0**

**2000**

**4000**

**6000**

**8000**

**10000**

**12000**

**Plasma ranolazine concentration, ng/mL **

**-100**

**-80**

**-60**

**-40**

**-20**

**0**

**20**

**40**

**60**

**80**

**100**

**ΔQTc vs averaged baseline, msec**

**Slope = 2.29 msec per 1000 ng/mL (R****2**** = 0.20)**

**The target concentration of 15,000 ng/mL could not be reached due to dizziness, nausea, postural hypotension, diplopia, somnolence, syncope, and paresthesia.**

**Individually optimized regressions of mean RR intervals and median QT intervals. ****Percentiles are peak concentrations on 1000 mg bid in CVT 3031 and CVT 3033 shown for comparison.**

## Study CVT 3111—Conclusions

**The relationship between ranolazine and ∆QTc remains linear at 2.29 msec per 1000 ng/mL over the entire achievable concentration range **
**A ranolazine concentration of 15,000 ng/mL could not be achieved in healthy volunteers due to the development of adverse events**
**Syncope was observed during continuous ECG monitoring with no arrhythmias**

## Population Analysis of Ranolazine Concentration vs QTc

**15 studies; 1308 subjects/patients; 15,819 ECGs**
**The ranolazine vs ********QTc relationship was again linear at 2.4 msec per 1000 ng/mL**
**The slope of the ranolazine vs ********QTc relationship was not altered by**
**Heart rate****	**–** Heart failure****	**–** Age**
**Gender****	**–** Diuretics****	**–** Anti-anginals**
**This is a different profile from drugs known to cause torsade de pointes (TdP)**
**The slope was 7 msec per 1000 ng/mL in patients with hepatic impairment (n = 16) **

## Fridericia QTc Outlier Values (Lead II) CVT 3031 - 3034

**Fridericia QTc Outlier Values (Lead II) ****CVT 3031 - 3034**

|  | Patients, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  |  | Ranolazine, mg bid |  |  |  |
|  | Placebo | 500 | 750 | 1000 | 1500 |
| Lead II QT |  |  |  |  |  |
| 	N | 422 | 647 | 694 | 609 | 162 |
| QTc > 500 msec | 1 (0.2) | 2 (0.3) | 2 (0.3) | 4 (0.7) | 1 (0.6) |
| QTc increase ≥ 60 msec from baseline | 3 (0.7) | 7 (1.1) | 6 (0.9) | 14 (2.3) | 6 (3.7) |
| Either | 3 (0.7) | 8 (1.2) | 7 (1.0) | 17 (2.8) | 7 (4.3) |
| Both | 1 (0.2) | 1 (0.2) | 1 (0.1) | 1 (0.2) | 0 |

**Baseline is the last observation prior to start of first dose.**

## Pharmacokinetics Are Well Characterized

**Kinetics unaffected by**
**Gender**
**Age **
**Food **
**Comorbidities (CHF, diabetes)**
**Atenolol, amlodipine, digoxin, simvastatin**
**Ranolazine is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 **

## Drug and Disease Interactions Are Well Described

**Drug and Disease Interactions ****Are Well Described**

## Clinical Events of Special Interest† With QTc ProlongationPhase 2/3 SR Controlled Studies

|  | Patients with events, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  |  | Ranolazine, mg bid |  |  |  |
|  | Placebo | 500 | 750 | 1000 | 1500 |
| Total patients, N | 455 | 181 | 279 | 459 | 187 |
| Preferred term |  |  |  |  |  |
|    Dizziness | 6 (1.3) | 2 (1.1) | 10 (3.6) | 29 (6.3) | 22 (11.8) |
|    Heart arrest | 1 (0.2) | 0 | 0 | 1 (0.2) | 0 |
|    Palpitation | 5 (1.1) | 0 | 2 (0.7) | 2 (0.4) | 4 (2.1) |
|    Sudden death | 2 (0.4) | 1 (0.6) | 1 (0.4) | 1 (0.2) | 0 |
|    Syncope | 0 | 0 | 0 | 5 (1.1) | 3 (1.6) |
|    Ventricular fibrillation | 0 | 1 (0.6) | 0 | 0 | 0 |
|    Ventricular tachycardia | 0 | 0 | 1 (0.4) | 0 | 0 |
|    Seizure | 0 | 0 | 0 | 0 | 0 |
|    Torsade de pointes | 0 | 0 | 0 | 0 | 0 |

**†****Preliminary concept paper.**

## Postural Hypotension and Syncope

**Postural hypotension**
**Dose related in volunteers**
**May be due to α****1****-adrenergic receptor blockade at higher concentrations**
**Syncope**
**Has been witnessed during continuous ECG monitoring with no arrhythmias**
**Patients with syncope more likely to be on vasoactive medications**
**No ECG evidence for torsade de pointes in patients with syncope**

## Frequency of SyncopePhase 2/3 Controlled and Long-Term Follow-up Studies

|  | Placebo |  | Ranolazine |
| --- | --- | --- | --- |
| Syncope rate/patient yr†, % | 1.0 |  | 2.1 |
| 95% CI | (0.03, 5.6) | (1.3, 3.1) |  |
| Patient yr | 97.1 | 1149.4 |  |

**†****Excluding patients on 1500 mg bid.**

## Summary—Ranolazine and Cardiac Repolarization

**The QTc effect of ranolazine is well characterized**
**At plasma concentrations exceeding tolerability**
**Remains linear at 2.4 msec per 1000 ng/mL **
**Intolerability limits exposure to concentrations associated with larger QTc increases**
**The cellular electrophysiology underlying the QTc effect of ranolazine is fundamentally different from that of drugs known to cause torsade de pointes**

## Dosing Rationale and Recommendations

**Ranolazine plasma concentration increases with increasing dose **
**Efficacy increases linearly **
**From 500 to 1500 mg bid in MARISA**
**With plasma concentration in a population analysis**
**Adverse events increase disproportionately from 1000 to 1500 mg bid**
**For most patients, initiate dosing at 500 mg bid and titrate as needed based on anti-anginal response through 750 mg bid to 1000 mg bid**