Review of Literature

REVIEW OF LITERATURE ON ANGINA PECTORIS AND RANOLIZINE

3.1. INTRODUCTION TO ANGINA PECTORIS

Angina pectoris is the medical term for chest pain or discomfort due to coronary heart
disease. Angina is a symptom of a condition called myocardial ischemia. It occurs when the
heart muscle (myocardium) doesn't get as much blood (hence as much oxygen) as it needs.
This usually happens because one or more of the heart's arteries (coronary blood vessels that
supply blood to the heart muscle) is narrowed or blocked. Insufficient blood supply is called
ischemia.

Types of Angina Pectoris

The types of angina are stable, unstable, variant (Prinzmetal's), and microvascular. Knowing
how the types differ is important. This is because they have different symptoms and require
differenttreatments.

StableAngina
Stable angina is a repeating pattern of chest pain which has not changed in character,
frequency, intensity or duration for several weeks (2, 8). The level of activity or stress that
provokes angina is predictable and the pattern changes slowly. Stable angina is the most
common form and it appears gradually. These patients have an increased risk of a heart attack,
but an episode of stable angina does not indicate that a heart attack is about tohappen.
UnstableAngina
Unstable angina is chest pain that is variable, either increasing in frequency or intensity and
with irregular timing or duration. Unlike stable angina, unstable angina does not appear
gradually, it first appears as a severe episode(8). An established stable angina might change
suddenly or be provoked by less stress than in the past or an episode might suddenly occur
while at rest. If the pattern of an episode changes, for example if a previous episode was only
brought on during physical exertion, but an episode suddenly occurred at rest it is likely to be
unstable angina
Prinzmetal'sAngina
Prinzmetal’s or variant angina is caused by a vasospasm, a spasm that narrows the coronary

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artery and lessens the blood flow to the heart (8). Prinzmetal's Angina usually occurs in
arteries already narrowed by atherosclerosis; in fact most people with it have severe coronary.
Mechanism of angina pectoris
A coronary atherosclerotic lesion is present in a branch of the left anterior descending
coronary artery. During exercise, blood flow through the narrowed area becomes inadequate
and the region of muscle supplied by that branch (stippled area) becomes ischemic, causing
chest pain or angina pectoris. (Drawing by G. Gloege. From Ross and O’Rourke,1976c.)

Figure 2: Human Heart

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Symptoms of angina
Symptoms typically start during physical exertion or emotional stress. They are often worse in
cold or windy weather and sometimes after big meals.
• A sense of heaviness or numbness in the arm, shoulder, elbow or hand, usually on the
left side.
• Increased shortness of breath on exercise.

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• A squeezing or heavy pressing sensation on the chest.

• The discomfort can radiate into both arms, the jaw, teeth, ears, stomach and in rare
cases between the shoulder blades.
• A constricting sensation in the throat.
Blood then clots around the rupture, and the clot may be large enough to block the artery and
seal off the blood supply. This may cause unstable angina or a heart attack.

Treatment
The main goals of treatment in angina pectoris are relief of symptoms, slowing progression of
the disease, and reduction of future events, especially heart attacks and of course death. An
aspirin (75 mg to 100 mg) per day has been shown to be beneficial for all patients with stable
angina that have no problems with its use. Beta blockers (eg. carvedilol, propranolol,atenolol
etc. are some few examples) have a large body of evidence in morbidity and mortality benefits
(fewer symptoms and disability and live longer) and short-acting nitroglycerin medications
are used for symptomatic relief of angina. Calcium channel blockers (such as nifedipine
(Adalat) and amlodipine), Isosorbide mononitrate and nicorandil are vasodilators commonly
used in chronic stable angina. A new therapeutic class, called If inhibitor, has recently been
made available: ivabradine provides pure heart rate reduction,. Leading to major anti-ischemic
and antianginal efficacy. ACE inhibitors are also vasodilators with both symptomatic and
prognostic benefit and lastly, statins are the most frequently used lipid/cholesterol modifiers
which probably also stabilise existing atheromatous plaque.

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3.2. RANOLAZINE DRUG PROFILE

Ranolazine- A Novel Therapeutic Option in Chronic Stable Angina
Chronic stable angina (CSA) represents the largest cardiovascular disorder in the United
States and is the initial clinical presentation of ischemic heart disease in 50% of patients. CSA
is the result of the progression of coronary atherosclerosis and becomes symptomatic once the
luminal diameter of the vessel is occluded by >50%. Current medical therapy is targeted at
reducing the frequency of anginal symptoms and improving exercise tolerance by increasing
myocardial oxygen supply via arteriole dilation (i.e., dihydropyridine calcium channel
blockers, nitrate therapy) and/or reducing myocardial oxygen demand by reducing heart rate
and contractility (i.e., non-dihydropyridine calcium channel antagonists and β-adrenergic
antagonists). Combinations of these agents can induce profound reductions in blood pressure
that limit the aggressive dosing needed in some CSA patients.
Ranolazine affords additional anti anginal and anti-ischemic efficacy in patients with severe
chronic angina who remain symptomatic while taking standard doses of atenolol, amlodipine,
or diltiazem, with minimal hemodynamic effects. It is of significant use in patients who
cannot tolerate the initiation or upward titration of currently available antianginal drugs
because of their depressive effects on blood pressure and heart rate.

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Drug Profile
Table 1: Ranolazine drug profile
Description White to off white solid
Form Crystalline powder
Chemical name 1-piperazineacetamide,N-(2,6-
dimethylphenyl)-4-[2-hydroxy-3-(2-
methoxyphenoxy)propyl]

Structure

Molecular formula C24H33N3O4,

Molecular Weight 427.54 g/mole
Melting point 120oC
Solubility Ranolazine is soluble in dichloromethane and
methanol; sparingly soluble in
tetrahydrofuran, ethanol, acetonitrile, and
acetone; slightly soluble in ethyl acetate,
isopropanol, toluene, and ethyl ether; and
very slightly soluble in water.
Therapeutic Category In the treatment of Angina pectoris
Pharmacopoeial Status I.H.S
Storage Conditions Store in air tight containers, Protect from
light

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Certificate of Analysis of Ranolazine

Table 2: Certificate of Analysis of Ranolazine

S. No. Test Specifications Results
1 Description A white to off white powder A white
crystalline powder crystalline
powder
2 Solubility sparingly soluble in methanol Complies
3 Identification The infrared absorption spectrum of Complies
the finely ground sample in KBR
dispersion compressible in to a disk
should exhibit maxima only at the
same wave length as that similar
preparation of working standard
4 Loss on Drying Not more than 0.5%w/w 0.23%w/w
5 Residue on Not more than 0.2%w/w 0.10%w/w
Ignition
6 Heavy metals Not more than 0.002%w/w Less
than0.002%w/w
7 Assay on dried Should be between 98.0% and 100.5%w/w
basis by HPLC 102.0%w/w

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Pharmacokinetics / Pharmacodynamics

Table 3: Pharmacokinetic / Pharmacodynamic Parameters of Ranolazine

Parameter Data
Time to peak serum concentration(Tmax) 2.0 to 6.0. hour
Bioavailability 32%-55%

Cmax 4 - 6hr
Biological half life 7 hour
Site and Mechanism of absorption and Absorption is highly variable (95% Cmax
distribution values ranged 420-6080 ng/mL)

Plasma protein binding Highlya-1 acid glycoprotein bound (65.3%)

Route of metabolism Extensively metabolized in the liver and
intestine. (Primarily by CYP 3A4 and to a
lesser extent 2D6).

Activity of metabolites Yes, 4 most abundant metabolites have

activity 5-33% thatif the parent compound

Route of excretion Urinary excretion is a primary route of

excretion of Ranolazine metabolites. (75%)
and feces (25%)
Route of administration oral

Mode of Action
Ranolazine is a free base and it has a has antianginal and anti-ischemic effects that do not
depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure
product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels
can inhibit the late INa. However, the relationship of this inhibition to angina symptoms is
uncertain.
The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of
inhibition of IKr, which prolongs the ventricular action potential

Pharmacokinetics

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Ranolazine is extensively metabolized in the gut and liver and its absorption is highly
variable. For example, at a dose of 1000 mg twice daily, the mean steadystate Cmax was 2600
ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+)
R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent
terminal half-life of ranolazine is 7 hours. Steady state is generally achieved within 3 days of
twice-daily dosing with ranolazine. At steady state over the dose range of 500 to 1000 mg
twice daily, Cmax and AUC0-μ increase slightly more than proportionally to dose, 2.2- and
2.4- fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine
plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine isunaffected by age,
gender, or food.
Absorption and distribution
After oral administration of Ranolazine, peak plasma concentrations of ranolazine are reached
between 2 and 5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the
dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine
from Ranolazine ER 500 mg tablets relative to that from a solution of ranolazine is 76%.
Because ranolazine is a substrate of P-glycoprotein (P-gp), inhibitors of P-gp may increase the
absorption of ranolazine.
Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine.
Therefore, Ranolazine may be taken without regard to meals. Over the concentration range of
0.25 to 10 µg/mL, ranolazine is approximately 62% bound to human plasma proteins.

Metabolism and excretion

Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is
excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not
been well characterized. Ranolazine is metabolized mainly by CYP3A and to a lesser extent
by CYP2D6.

Drug-Drug Interactions of Ranolazine

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Table 4: Drug Interactions of Ranolazine

Objective drug Comments
Drugs which effects on bioavailability of Dilitazem,ketoconazole,verapamil,
Ranolazine cimetidine,paroxetine
Drugs which increase the plasma Digoxin,simvastatin,warfarin
concentration

3.3. LITERATURE REVIEW OF RANOLAZINE

Wolff, Andrew A (2005) (San Francisco,) studied on “Methods for treating angina with
ranolazine” A sustained release ranolazine formulation contains an intimate mixture of
ranolazine and a partially neutralized pH-dependent binder to form a film that is mostly
insoluble in aqueous media below pH 4.5 and soluble in aqueous media above pH 4.5. The
formulation is suitable for twice daily administration of ranolazine and is useful for
controlling the rate of dissolution of ranolazine, and to maintain human plasma ranolazine
levels at between 850 and 4000 ng base/mL.

Siddiqui et. Al., (2006) proved that Comparative trials of ranolazine ER with other
antianginal agents and trials examiing its effects on long-term morbidity and mortality in
patients with ischaemic heart disease are required to determine with greater certainty the place
of the drug in current antianginal therapy. Nevertheless, ranolazine ER may well prove to be a
useful alternative and adjunct to conventional haemodynamic antianginal therapy in the
treatment of chronic stable angina.

Markus Jerling MD, et. al., (2004) was proved to Effect of renal impairment on multiple-
dose pharmacokinetics of extended-release ranolazine*”Ranolazine is a novel compound
under development as an antianginal agent. The multiple-dose pharmacokinetics of extended-
release ranolazine and 3 major metabolites was investigated in healthy subjects (N = 8) and
subjects with mild to severe renal impairment (N = 21). The ranolazine AUC0-12 (area under
the concentration-time curve between 0 and 12 hours after dosing) geometric mean ratio
versus healthy subjects at steady state was 1.72 (90% confidence interval [CI], 1.07-2.76) in
subjects with mild impairment, 1.80 (90% CI, 1.13-2.89) in those with moderate impairment,
and 1.97 (90% CI, 1.23-3.16) in those with severe renal impairment. Creatinine clearance was
negatively correlated with AUC0-12 and the maximum observed concentration for ranolazine

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and the O-dearylated metabolite (P<.05 for all variables), as well as the N-dealkylated
metabolite (P<.001), but not for the O-demethylated metabolite. 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. No serious adverse events were observed in the study.

William B. Smith et.al., (2003) “A Multicenter Controlled Trial of a Novel Metabolic Active
Compound (Ranolazine) in Chronic Stable Angina Patients”Ranolazine significantly
increased times to onset of both angina and ST segment depression at all doses tested. All
exercise parameters were significantly (P ≤ 0.01) improved with ranolazine at peak plasma
levels compared with placebo as ranolazine plasma levels ranged from 1,350 to 2,130 ng
base/mL. No significant differences between ranolazine and placebo were observed at trough
with mean ranolazine plasma levels ranging from 235 to 514 ng base/mL. No clinically
meaningful hemodynamic changes or adverse events occurred with ranolazine compared with
placebo. In summary, ranolazine was well tolerated over a wide range of plasma levels.
Ranolazine increased exercise times with no detectable effect on cardiac hemodynamics in
patients with chronic stable angina taking other antianginal drugs.

Bharti Bhandari and Subramanian Loganathan (2005) were worked on “Ranolazine, a

Partial Fatty Acid Oxidation Inhibitor, its Potential Benefit in Angina and other
Cardiovascular Disorders”Ranolazine has been approved by US FDA for the treatment of
chronic angina pectoris in combination with amlodipine, β-blockers or nitrates in patients who
do not show adequate response to other anti-anginals. Ranolazine is a metabolic modulator
that is being developed by CV Therapeutics (CVT), under license from Roche (formerly
Syntex), as a potential treatment for angina. Ranolazine is available as brand name ‘Ranexa”
as extended release oral tablets. This review focuses on the clinical effects, the mechanism of
actions, drug interactions and beneficial effects of Ranolazine in chronic angina and other
cardiometabolic disorders.

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Mohammad J Tafreshi, Edward Fisher (2006) Studied on Ranolazine:

(April”
A New Approach to Management of Patients with Angina Ranolazine
has a unique mechanism of action that is different from that of
conventional agents. It has been studied as monotherapy or in combination
with other commonly prescribed agents. It appears that ranolazine has a
promising safety data profile and does not affect hemodynamic parameters.
At this point, although ranolazine should not be used in place of
conventional therapy, it appears that ranolazine may be considered in the
management of symptomatic patients when standard antianginal
medications are not tolerated or are ineffective.

Zerumsky K, McBride BF(2006) “Ranolazine in the management of chronic stable

angina”. Ranolazine has recently been approved as adjunctive treatment for chronic stable
angina (CSA). Data suggest that ranolazine exerts its antiischemic effect through antagonism
of the late sodium current and other cardiac ion channels. Peak plasma levels of ranolazine
have been observed two to five hours following repeated dosing and are unaffected by food.
In placebo-controlled and active-controlled clinical trials conducted with ranolazine,
ranolazine has been effective in the treatment of patients with CSA. One trial demonstrated
that monotherapy with extended-release ranolazine was effective against angina and ischemia
in patients with CSA. Ranolazine improved exercise duration and time to onset of angina. In a
trial in which ranolazine was given in combination with atenolol, diltiazem, or amlodipine,
ranolazine produced clinically significant improvement in exercise duration and reduced the
incidence of anginal attacks compared with placebo. Another trial demonstrated that
extended-release ranolazine 1000 mg given twice daily reduced mean weekly angina episodes
in patients with chronic angina. Ranolazine is generally well tolerated. In clinical trials,
adverse effects were seen more in the ranolazine groups than in the placebo groups.

W.M. Cheng(2006)” Ranolazine for the management of coronary artery disease”.

Ranolazine is a new antianginal agent that is effective in the management of chronic angina.
Its unique mechanism of action warrants further study in other cardiovascular conditions such
as heart failure and arrhythmias. Ongoing studies will address whether ranolazine can reduce
clinical end points such as cardiovascular death and myocardial infarction.Ranolazine is a cell
membrane inhibitor of the late sodium current. Extended-release ranolazine was recently
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approved in the United States for the treatment of chronic angina. Ranolazine is metabolized
in the liver by the cytochrome P-450 (CYP) 3A4 system. Because of its potential to prolong
corrected QT (QTc) intervals, ranolazine should not be used in patients with hepatic
impairment, those with QTc prolongation, or those taking drugs known to prolong QTc
intervals or drugs that are potent CYP 3A4 inhibitors. Other adverse effects of ranolazine
include dizziness, headache, constipation, and nausea. Placebo-controlled clinical studies
performed to date have found that sustained-release ranolazine 500 to 1500 mg PO BID was
associated with significantly increased time to onset of angina (range of increase, 27.0–144.0
s; P < 0.05 [varied among studies]), exercise duration (range of increase, 23.8–99.0 s; P <
0.05 [varied among studies] ), and time to 1-mm ST depression (range of increase, 27.6–146.2
s; P < 0.05 [varied among studies]). In addition, exercise duration was found to be
significantly longer with ranolazine compared with atenolol (453 vs 430 s; P = 0.006).

MERLIN TIMI-36(2006) “CV Therapeutics Completes MERLIN TIMI-36

Study”

(Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute
Coronary Syndromes) is a multi-national, double-blind, randomized, placebo-controlled,
parallel-group clinical trial designed to evaluate the efficacy and safety of Ranexa during
acute and long-term treatment in approximately 6,500 patients with non-ST elevation ACS
treated with standard therapy. Within 48 hours of the onset of angina due to ACS, eligible
hospitalized patients were enrolled in the study and randomized to receive intravenous Ranexa
or placebo, followed by long-term outpatient treatment with Ranexa extended-release tablets
or placebo. All patients also received standard therapy during both hospital-based and
outpatient treatment. The doses of Ranexa extended-release tablets used in MERLIN TIMI-36

have been studied in previous phase 3 clinical trials. Currently, Ranexa is indicated for the
treatment of chronic angina in patients who have not achieved an adequate response with
other antianginal drugs, and should be used in combination with amlodipine, beta-blockers or
nitrates.

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Wyatt KM, McCormack JG (1996) “Ranolazine increases active pyruvate dehydrogenase in

perfused normoxic rat hearts: evidence for an indirect mechanism”Ranolazine has shown
anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but
without affecting haemodynamics or baseline contraction. In isolated normoxic rat
hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM
or 0.8 mM palmitate, 20 microM ranolazine significantly increased active,
dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2
mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly
increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate.
PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and
additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine
and promotion of glucose oxidation offers a plausible means by which the drug may be
anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and
isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH
kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known
effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates
PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl
CoA content under all conditions where fatty acid was present, and +/- DCA which itself
had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA.
In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still
decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused
hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine.
This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation
leading to decreased acetyl CoA and activation of PDH.

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Anderson JR, Khou S, Nawarskas JJ(2001). Ranolazine: a potential new treatment for
chronic stable angina. Ranolazine is a novel antianginal agent currently under
investigation as monotherapy and adjunct therapy for the treatment of chronic stable
angina. Although the mechanism of action of ranolazine is not completely understood, it
is believed to involve a reduction in fatty acid oxidation, ultimately leading to a shift in
myocardial energy production from fatty acid oxidation to glucose oxidation. Because
the oxidation of glucose requires less oxygen than the oxidation of fatty acids, ranolazine
can help maintain myocardial function in times of ischemia. In addition, ranolazine does
not significantly affect blood pressure, heart rate, or cardiac conduction. The clinical
data with ranolazine focuses on its use in chronic stable angina, where it has been shown
to increase exercise tolerance and decrease angina compared with placebo and in
combination with beta-blockers and calcium-channel blockers. The use of ranolazine for
other cardiac conditions and the effect of ranolazine on morbidity and mortality remain
to be determined.

Chaitman BR, Skettino SL, Parker JO, et al(2004) studied on Anti-ischemic effects and
long-term survival during ranolazine monotherapy in patients with chronic severe angina. In
this largest study of ranolazine in patients with established coronary artery disease, ranolazine
was effective in reducing angina with favorable safety in a substantially broader group of
patients with angina than previously studied. (Metabolic Efficiency With Ranolazine for Less
Ischemia in Non-ST Elevation Acute Coronary Syndromes;

Nickole N. Henyan, PharmD, C. Michael White, PharmD(2005) “Ranolazine: An update on

the novel antianginal agent” Ranolazine (Ranexa, CV Therapeutics) is a partial fatty acid oxidase
inhibitor that increases the amount of ATP produced from glucose and increases the ability of
the myocardium to retain functionality despite a reduced oxygen supply. Ranolazine is under
FDA review for the treatment of chronic stable angina (CSA). Ranolazine was first reviewed
in the August 2003 issue of Formulary. Since the initial review of ranolazine by FDA,
additional data have emerged that merit an update in this journal. Clinical trials have
demonstrated the efficacy of ranolazine as both monotherapy and combination therapy in
patients with CSA. Recently published clinical trials (MARISA and CARISA) have shown an
improvement in symptom-limited exercise duration. The results of the ERICA trial
demonstrated a reduction in weekly anginal attacks when ranolazine was added to maximum-
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dose amlodipine therapy. Headache and generalized weakness were the most commonly
reported adverse events in clinical trials. Prolongation of the QT interval has raised concerns;
however, a lack of development of ventricular tachyarrhythmias—specifically Torsade de
Pointes—remains an important safety finding.

Charles Antzelevitch, PhD; Luiz Belardinelli, MD; Andrew C. Zygmunt, PhD et al

(2004) “Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With
Antiarrhythmic Properties”Ranolazine is a novel antianginal agent capable of producing
antiischemic effects at plasma concentrations of 2 to 6 µmol/L without reducing heart rate or
blood pressure. The present study examines its electrophysiological effects in isolated canine
ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations.
Ranolazine produces ion channel effects similar to those observed after chronic amiodarone
(reduced IKr, IKs, late INa, and ICa). The actions of ranolazine to suppress EADs and reduce TDR
suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic
activity.

Jerling M, Huan B, Leung K, Chu N, et al(2005) “Studies to Investigate the

Pharmacokinetic Interactions Between Ranolazine and Ketoconazole, Diltiazem, or
Simvastatin During Combined Administration in Healthy Subjects” The interactions of
ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A
isoenzyme family were studied in 1 open-label and 4 double-blind, randomized, multiple-dose
studies. In healthy adult volunteers, the authors sought (1) to determine the steady-state
pharmacokinetics, safety, and tolerability of immediate- and sustained-release ranolazine with
and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine
on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG-CoA
reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the
CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the
primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a
dose-dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although
ranolazine increased the AUC and Cmax of simvastatin, simvastatin acid, 2 simvastatin
metabolites, and HMG-CoA reductase activity by <2-fold. Administration of ranolazine in
combination with diltiazem or simvastatin was safe and well tolerated during the interval
studied.
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