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REVIEW OF A NEW ANTI-
PLATELET AGENT: FOCUS ON
PRASUGREL

Jimmy Butt, Pharm.D. Candidate


Acute coronary syndrome (ACS) generally refers
to a group of clinical symptoms associated
with acute myocardial ischemia.1 ACS, which
includes heart attacks and unstable angina, affects
nearly 1.5 million people in the United States annually,
many of whom are managed with percutaneous coro-
nary intervention (PCI).2 In 2009, an estimated
785,000 people in the United States will have a first
heart attack and 470,000 will have a recurrent attack.3
Current therapy for patients presenting with
acute myocardial ischemia include MONA (morphine,
oxygen, nitroglycerin, aspirin).4 Clopidogrel (Plavix),
a thienopyridine, can be used instead of or in addition
to aspirin.4 Prasugrel (Effient) is a 3rd generation
thienopyridine manufactured by Daiichi Sankyo and
distributed by Eli Lilly in the United States. A direct
competitor to clopidogrel, prasugrel was approved on
July 10, 2009 for the reduction of thrombotic cardio-
vascular events (including stent thrombosis) in pa-
tients with ACS who are managed with PCI.5 This arti-
cle will review the safety and efficacy of prasugrel as
an option for reducing cardiovascular events in pa-
tients with ACS managed with PCI.

PHARMACOLOGY

Prasugrel inhibits adenosine diphosphate (ADP)
induced platelet aggregation.6 Prasugrel, similar to
clopidogrel, is an inactive prodrug which undergoes


hepatic conversion to its active metabolite in a single
rapid step process.6,7 The active metabolite (R-
138727) irreversibly binds and antagonizes the plate-
let P2Y12 receptor for the life of the platelet, thus pre-
venting ADP binding.8,9 With ADP unable to bind to
the platelet, activation of glycoprotein IIb/IIIa (Glib/
IIIa) complex is impaired, ultimately reducing fibrino-
gen binding and platelet aggregation.6,8

PHARMACOKINETICS

Prasugrel is extensively (L 79%) and rapidly ab-
sorbed with peak plasma concentrations occurring 30
minutes after ingestion (Table 1). Following oral ab-
sorption, prasugrel is converted to its active metabo-
lite via hydrolysis by intestinal carboxylesterases and
subsequent oxidation by hepatic cytochrome P450
enzymes primarily CYP3A4 and CYP2B6 and to a
lesser extent CYP2C9 and CYP2C19.6,7,9 The active me-
tabolite is 98% bound to albumin and has an esti-
mated volume of distribution of 44-68 L. 6,7 The ac-
tive metabolite has an elimination half life of ~8 hours
with clearance occurring via a secondary metabolism
to two inactive compounds.6,7 These inactive com-
pounds are then excreted in the urine (70%) and feces
(25%).6,7 Repeated daily doses of 10 mg do not lead to
accumulation of the active metabolite.7






INSIDE THIS ISSUE:

REVIEW OF A NEW ANTI-PLATELET AGENT:
FOCUS ON PRASUGREL


mm


PharmaNote


VOLUME 25, ISSUE 4 JANUARY 2010
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Volume 25, Issue 4 1 January 2010


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Table 1. Pharmacokinetic properties of prasugrel.6
PROPERTY PRASUGREL
ONSET 15-30 mins
TIME TO PEAK CONCENTRATION 30 mins
TIME TO PEAK RESPONSE 2 hours
DURATION 5 days
BIOAVAILABILITY 79% (rapidly absorbed)
METABOLISM Rapid & extensive via liver
EXCRETION Renal (70%) & Feces (25%)
T1/2 ~ 8 hours


CLINICAL TRIALS

Clinical Efficacy & Safety Studies
Jernberg and colleagues conducted a randomized
(with stratification), single-blind, parallel-group study
in patients (n = 101) with CAD who were taking aspi-
rin. Patients were male and female, between the ages
of 40-75 years. The primary endpoint of the study was
to characterize, in aspirin-treated subjects with stable
CAD, the degree of inhibition of platelet aggregation
(IPA) associated with four dosing regimens of pra-
sugrel compared with the currently approved clopido-
grel loading dose (LD) + maintenance dose (MD) regi-
men. Patients were randomly assigned to oral pra-
sugrel 40/5, 40/7.5, 60/10 or 60/15 mg LD/MD or
oral clopidogrel 300/75 mg LD/MD for 28 days. The
investigators found that 4 hrs after dosing, with 20
mM ADP, both prasugrel 40 and 60 mg LDs achieved
significantly higher mean IPA levels than clopidogrel
300 mg LD (60.6% and 68.4 vs. 30.0%, respectively; all
P < 0.0001). Moreover, the prasugrel group contained
lower a percentage (3% vs. 52%, P < 0.0001) of phar-
macodynamic non-responders (defined as IPA, 20%)
than clopidogrel. By day 28, prasugrel 10 and 15 mg
MDs achieved consistently higher mean IPA than clopi-
dogrel 75 mg (all P < 0.0001). At pre-MD on day 28, no
non-responders were observed in the 10 and 15 mg
prasugrel group, compared with 45% of subjects in the
clopidogrel group (P = 0.0007). The study concluded
that prasugrel (40-60 mg LD and 10-15 mg MD)
achieves greater IPA and a lower proportion of phar-
macodynamic non-responders compared with the ap-
proved clopidogrel dosing.11
The JUMBO-TIMI 26 was a phase II clinical trial
that enrolled 904 patients undergoing elective or ur-
gent PCI.12 In this double-blind, dose-ranging safety
trial, patients were randomly allocated to prasugrel or
clopidogrel and monitored for 30 days for bleeding
and clinical events. The primary endpoint was clini-
cally significant (TIMI major plus minor) non-CABG-


related bleeding events. Patients were treated with
oral prasugrel 40/7.5, 60/10 or 60/15 mg LD/MD or
oral clopidogrel 300/75 mg LD/ MD for 30 days. Hem-
orrhagic complications were infrequent, with no sig-
nificant difference between treatment groups in the
rate of significant bleeding (1.7% prasugrel versus
1.2% clopidogrel; hazard ratio, 1.42; 95% CI, 0.40,
5.08). No significant difference was observed between
groups for the primary efficacy composite end point
(30-day major adverse cardiac events) and several
secondary end points, including myocardial infarction,
recurrent ischemia, and clinical target vessel thrombo-
sis. Prasugrel treatment was associated with a non-
significant decrease in major adverse cardiac events
(9.4 and 7.2% for clopidogrel and prasugrel, respec-
tively), including death, stroke and myocardial infarc-
tion. The study was underpowered due to the lower
than expected bleeding rates in both groups, but
would set the stage for the larger, phase III TRITON-
TIMI 38 trial.

Comparative Efficacy & Safety Studies
TRITON-TIMI 38, a phase III trial, compared pra-
sugrel with clopidogrel in 13,608 patients with moder-
ate-to-high-risk ACS and scheduled PCI.12 Patients
were studied for 6 to 15 months for the primary com-
posite endpoint of death from cardiovascular causes,
nonfatal myocardial infarction, or nonfatal stroke. The
key safety end point was major bleeding. Patients re-
ceived oral prasugrel 60/10 mg LD/MD or oral clopi-
dogrel 300/75 mg LD/MD for 12 months. The primary
efficacy end point occurred in 12.1% of patients re-
ceiving clopidogrel vs. 9.9% of patients receiving pra-
sugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81;
95% confidence interval, 0.73 to 0.90; P<0.001). The
investigators found significant reductions in favor of
prasugrel in the rates of myocardial infarction (9.7%
for clopidogrel vs. 7.4% for prasugrel; P<0.001), ur-
gent target-vessel revascularization (3.7% vs. 2.5%;
P<0.001), and stent thrombosis (2.4% vs. 1.1%;
P<0.001). However, major bleeding occurred in 2.4%
of patients receiving prasugrel vs. 1.8% of patients re-
ceiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to
1.68; P=0.03). In addition, the rate of life-threatening
bleeding was greater in the prasugrel group (1.4% vs.
0.9%; P=0.01), including nonfatal bleeding (1.1% vs.
0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding
(0.4% vs. 0.1%; P=0.002).15 The increase in life-
threatening bleeding prompted the FDA to include a
box warning on prasugrel's label.
To date, no published studies address prasugrel's
possible use for decreasing cardiovascular events
(heart attack or stroke) in those without PCI (Table 2).
TRILOGY ACS (TaRgeted platelet Inhibition to cLarify


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Volume 25, Issue 4 1 January 2010


PharmaNote







Table 2. Summary of clinical trials of prasugrel.


STUDY
Jernberg, et al."
(2006)








Wiviott, et al.12
(2005)








Wiviott, et al.13
(2007)




Wallentin L, et al.14
(2008)








Wiviott SD, et al.15
(2007)


DESIGN
. Study in CAD patients (n=101) on ASA.
. Randomized, single-blind, parallel-group.
. History of CAD, aged 40-75 years.
. Primary Endpoint: IPA with 4 dosing regimens
of prasugrel vs. clopidogrel LD and MD.





. Phase II in patients (n = 904) undergoing PCI.
. Randomized, dose-ranging, double-blind safety
trial of prasugrel vs. clopidogrel.
. Monitored 30 days for bleeding and clinical
events.
. Primary Endpoint: Clinically significant
(TIMI major plus minor) non-CABG-related
bleeding events in prasugrel vs. clopidogrel
patients.
. Randomized, double-blind, phase II crossover
study for planned PCI (n = 201)
. Primary Endpoint: Loading-dose phase
(prasugrel 60 mg vs. clopidogrel 600mg) was
IPA with 20 Imol/L ADP at 6 hrs.
. Phase II in patients (n = 110) with stable CAD,
randomized to double-blind treatment with
clopidogrel or prasugrel
. Determined concentrations of prasugrel and
clopidogrel active metabolites.
. Primary Endpoint: Platelet aggregation reported
as MPA and P2Y12 function were assessed.


. Phase III to compare prasugrel with clopidogrel,
in patients (n=13,608) with moderate-to-high-
risk ACS with scheduled PCI.
. Primary Endpoint: Death from cardiovascu-
larcauses, nonfatal myocardial infarction, or
nonfatal stroke. The key safety end point was
major bleeding.


Table 2. Summary of clinical trials of prasugrel.


IPA = Inhibition of Platelet Aggregation, LD = Loading Dose, MD= Maintenance Dose, TIMI = Thrombolysis In Myocardial Infarction, MPA = Maximal Platelet Aggregation.


DOSE
. Prasugrel 40/5, 40/7.5, 60/10 or 60/15
mg LD/MD
. Clopidogrel (300/75 mg LD/MD) for 28
days
. Ex vivo ADP-induced MPA was serially
assessed.




. Prasugrel 40/7.5, 60/10 or 60/15 mg LD/
MD
. Clopidogrel 300/75 mg LD/ MD for ap-
proximately 30 days






. Prasugrel 60/10 mg LD/MD or
. Clopidogrel 600/150 mg LD/MD for 14
days.


. Pretreated with aspirin (75 mg) then re-
ceived either prasugrel 60/10 mg LD/MD
or clopidogrel 600/75 mg LD/MD for 28
days.






. Patients received prasugrel (60/10 mg
LD/MD) or clopidogrel (300/75 mg LD/
MD) for approximately 12 months (range
6 to 15 months)


RESULTS
. 4 hrs after dosing, prasugrel LDs had significantly higher mean
IPA levels vs. clopidogrel (60.6% and 68.4 vs. 30.0%; all P <
0.0001)
. 4 hrs after dosing, fewer pharmacodynamic non-responders
than clopidogrel (3 vs. 52%, P < 0.0001)
. Prasugrel 10 and 15 mg MDs had higher mean IPA vs. clopido-
grel 75 mg at day 28 (all P < 0.0001).
. Day 28, no non-responders in the 10 and 15 mg prasugrel vs.
45% in the clopidogrel (P = 0.0007).
. No significant difference between prasugrel or clopidogrel in
the rate of significant bleeding (1.7% versus 1.2%; hazard ra-
tio, 1.42; 95% Cl, 0.40, 5.08).
. Prasugrel group had lower incidences of primary efficacy com-
posite end point (30-day major adverse cardiac events) and of
the secondary end points myocardial infarction, recurrent
ischemia, and clinical target vessel thrombosis.


. IPA at 6 hours was significantly higher in subjects receiving
prasugrel (meanSD, 74.813.0%) vs. clopidogrel
(31.821.1%; P<0.0001).
. MD phase, prasugrel was higher (61.317.8%) vs. clopidogrel
(46.121.3%; P<0.0001).
. 2 h post-LD, mean MPA was 31% vs. 55%, and mean PRI 8.3%
vs. 55.9% for prasugrel and clopidogrel, (P < 0.001).
. MD on day 14 and 28, mean MPA was 42 vs. 54% and
mean PRI was 25 vs. 51% (P < 0.001).
. Peak level of the active metabolite and P2Y12 inhibition oc-
curred earlier and greater with prasugrel (P < 0.001).
. Mean AUC of active metabolite was higher with prasugrel vs.
clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs.
0.062).
. Primary efficacy end point occurred in 12.1% in clopidogrel
group vs. 9.9% in prasugrel group (hazard ratio for prasugrel
vs. clopidogrel, 0.81; 95% confidence interval, 0.73 to 0.90;
P<0.001).
. Significant reductions in the prasugrel group in rates of MI
(9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent
target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and
stent thrombosis (2.4% vs. 1.1%; P<0.001).
. Major bleeding in 2.4% of prasugrel group vs. 1.8% of clopido-
grel group (hazard ratio, 1.32; 95% Cl, 1.03 to 1.68; P=0.03).
. Rate of life-threatening bleeding was 1.4% in prasugrel group
vs. 0.9% in clopidogrel group (P=0.01).







Table 3.Bleeding episodes stratified by age and weight.7,'15
MAJOR/MINOR BLEEDING FATAL
Prasugrel (%) Clopidogrel (%) Prasugrel (%) Clopidogrel (%)
Weight < 60kg (N=308 prasugrel, N=356 clopidogrel) 10.1 2.5 0 0.3
Weight 60kg (N=6373 prasugrel, N=6299 clopidogrel) 4.2 6.3 0.3 0.1
Age < 75 years (N=5850 prasugrel, N=5822 clopidogrel) 3.8 2.9 0.2 0.1
Age 75 years (N=891 prasugrel, N=894 clopidogrel) 9 6.9 1 0.1


the Optimal strateGy to medicallY manage Acute Coro-
nary Syndromes) trial is an ongoing multi-center, dou-
ble-blind, randomized controlled trial that will include
approximately 10,000 patients at more than 800 hos-
pitals in 35 countries to compare aspirin and pra-
sugrel vs. aspirin and clopidogrel.16,17 The primary
outcome will be a reduction in risk of the composite
endpoint of first occurrence of CV death, MI, or
stroke.17 TRILOGY-ACS is the first study to evaluate
the clinical efficacy of prasugrel in medically managed
patients with UA/NSTEMI. The expected completion
date is October 2011.17

SAFETY ISSUES

Box Warning
The FDA has added a box warning for prasugrel
due to an increased risk of significant, sometimes fatal,
bleeding. Prasugrel is contraindicated in patients with
active pathological bleeding or a history of transient
ischemic attack or stroke. 7 The TRITON-TIMI 38 trial
found that patients _> 75 years of age had an increased
risk of major/minor and fatal bleeding compared with
younger patients (Table 3).7,15
Prasugrel is also contraindicated in patients that
undergo urgent coronary artery bypass graft surgery
(CABG).6,7 In TRITON-TIMI 38, patients who under-
went CABG (n = 437) had a significantly higher rate of


major and minor bleeding when treated with pra-
sugrel (14%) compared with clopidogrel (4%).9,15
When possible, discontinue prasugrel at least 7 days
prior to any surgery. However, discontinuing pra-
sugrel in the first few weeks of ACS puts the patient at
risk for stent thrombosis, myocardial infarction, and
death. Thus, within this time frame, bleeding should be
managed without discontinuing prasugrel if possible.
In TRITON-TIMI 38, non-CABG related bleeding
occurred more often in prasugrel-treated patients
than those receiving clopidogrel (Table 4). However,
non-bleeding adverse events generally occurred at a
similar rate between the two treatment groups (Table
5).
Prasugrel is a substrate for CYP3A4, CYP2B6,
CYP2C9, and CYP2C19 as well as a weak inhibitor of
CYP2B6. Prasugrel is not expected to affect the phar-
macokinetics of medications with CYP2B6 mediated
metabolism. Prasugrel may be administered with
medications that are inducers or inhibitors of the cyto-
chrome P450 enzymes. 6,7 Concomitant treatment
with ketoconazole, a CYP3A4 inhibitor, reduced the
peak serum concentration of both prasugrel and clopi-
dogrel active metabolites by ~50%. The area under
the curve (AUC) of prasugrel and its IPA was not sig-
nificantly changed, but the AUC of clopidogrel was sig-
nificantly lower and its IPA was reduced 20%.18


Table 5. Bleeding events not related to CABG in TRITON-TIMI 38.7
Prasugrel (%) Clopidogrel (%) P-value for
ADVERSE EVENT (N=6741) (N=6716) comparison
TIMI Major or Minor bleeding 4.5 3.4 0.002
TIMI Major bleeding 2.2 1.7 0.029
Life-threatening 1.3 0.8 0.015
Fatal 0.3 0.1
Symptomatic intracranial hemorrhage 0.3 0.3
Requiring inotropes 0.3 0.1
Requiring surgical intervention 0.3 0.3
Requiring transfusion (_4 units) 0.7 0.5
TIMI Minor bleeding 2.4 1.9 0.022

riPh Nai \I OflIU


U1110 00U0 C3"Ualy


ra ma ote







Table 4. Non-hemorrhagic adverse events in TRITON
-TIMI 38.7


ADVERSE EVENT
Hypertension
Hypercholesterolemia
Headache
Back pain
Dyspnea
Nausea
Dizziness
Cough
Hypotension
Fatigue
Non-cardiac chest pain
Atrial fibrillation
Bradycardia
Leukopenia (< 4 x 109 WBC/L)
Rash
Pyrexia
Peripheral edema
Pain in extremity
Diarrhea


Prasugrel
(%)
(N=6741)
7.5
7.0
5.5
5.0
4.9


Clopidogrel
(%)
(N=6716)
7.1
7.4
5.3
4.5
4.5


Table 6. Average retail cost of prasugrel per month.

PRODUCT AVERAGE PRICE RANGE

Effient 5 mg $192.25 $185.99-$200.25

Effient 10 mg $196.50 $189.99-$204




SUMMARY

Antiplatelet medications reduce thrombotic cardio-
vascular events in patients with ACS undergoing PCI.
Prasugrel has a significantly higher IPA than clopido-
grel and produces fewer non-responders. However,
prasugrel has a box warning (bleeding), is contraindi-
cated in patients >75, and safety in patients < 60 kg
remains unclear. At the time of this publication, the
TRILOGY ACS trial is ongoing evaluating prasugel for
reduction of stroke, myocardial infarction, and death
in patients not undergoing PCI. The results of this trial
should shed further light on the appropriate use of
prasugrel in clinical practice.


REFERENCES


DOSING, ADMINISTRATION & COST

The recommended dose for arterial thromboem-
bolism prophylaxis in patients with ACS to be man-
aged with PCI that are > 60 kg and < 75 years of age is
60 mg PO as a loading dose, then 10 mg PO once
daily.6,7 The optimal duration of therapy is not known.
Patients should take concomitant aspirin 75-325
mg/day. Antiplatelet therapy should be promptly ad-
ministered in the management of ACS as many cardio-
vascular events occur within hours of initial presenta-
tion.
The manufacturer recommends a loading dose of
60 mg and a maintenance dose of 5 mg PO once daily
for patients < 60 kg and <75 years of age, although this
dose has not been prospectively studied for safety and
efficacy.6'9,10 Compared to heavier individuals, patients
weighing < 60 kg have an increased exposure to the
active metabolite and an increased risk of bleeding
when given 10 mg PO once daily.7 Prasugrel can be
administered with or without food, but tablets should
not be broken.6,7 The cost of prasugrel approaches
$200 monthly, regardless of strength (Table 6).


1. Acute Coronary Syndrome. American Heart Asso-
ciation, 2009. http://www.americanheart.org/
presenter.jhtml?identifier=3010002. Accessed
October 16, 2009.
2. American Heart Association. Heart Disease and
Stroke Statistics 2008 Update. Dallas, TX. Ameri-
can Heart Association. (Pg. 14)
3. American Heart Association Heart Disease and
Stroke Statistics 2009 Updated. Dallas, TX.
American Heart Association
4. Elliott M. Antman, Daniel T. Anbe, Paul Wayne
Armstrong, et al. ACC/AHA Guidelines for the Man-
agement of Patients With ST-Elevation Myocardial
Infarction. Circulation 2004;110: e82-293e.
5. Hull Tammy, Wix Kimberly, Kondo Shigemichi,
Effient Product Avaliability. Daiichi Sankyo Press
Release. Aug 5, 2009. http://www.dsi.com/news/
pdfs/Effient_Product_AvailabilityRelease.pdf. Ac-
cessed October 16, 2009.
6. Clinical Pharmacology [database online]. Tampa,
FL: Gold Standard, Inc.; 2009. URL: http://
www.clinicalpharmacology.com. Accessed 9/09.
7. Effient (prasugrel) package insert. Indianapolis,
IN: Eli Lilly and Company and Daiichi Sankyo, INC;
2009 July


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Volume 25, Issue 4 i January 2010


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8. Frelinger, A. Jakubowskim J, Barnard, M. et al. The
active metabolite of prasugrel inhibits adenosine
diphosphate- and collagen-stimulated platelet pro-
coagulant activities. Journal of Thrombosis and
Haemostasis 2008;6(2):359-65.
9. Bhatt DL. Prasugrel in clinical practice. N Engl J
Med 2009;361(10):940-942.
10. Micromedex Healthcare Series [Internet data-
base]. Greenwood Village, Colo: Thomson Reuters
(Healthcare) Inc. Updated periodically. Accessed
October 16, 2009.
11. Jernberg T, Payne CD, Winters KJ, et al. Prasugrel
achieves greater inhibition of platelet aggregation
and a lower rate of non-responders compared
with clopidogrel in aspirin-treated patients with
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2006;27(10):1166-1173.
12. Wiviott SD, Antman EM, Winters KJ, et al. Random-
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clopidogrel in percutaneous coronary interven-
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13. Wiviott SD, Trenk D, Frelinger AL, et al Prasugrel
compared with high loading- and maintenance-
dose clopidogrel in patients with planned percuta-
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(25):2923-32.
14. Wallentin L, Varenhorst C, James S, et al. Prasugrel
achieves greater and faster P2Y12 receptor- medi-
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16. Isert, Joedy. Straat, Jo-ann. Kondo, Shigemichi. Dai-
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www.dsi.com/news/pdfs/TRILOGY.pdf. Accessed
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17. Eli Lilly. A Comparison of Prasugrel and Clopido-
grel in Acute Coronary Syndrome Subjects
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2009. http://clinicaltrials.gov/ct2/show/study/
NCT00699998. Accessed October 16, 2009.


18. Farid NA, Payne CD, Small DS, Winters KJ, et
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