Spaced administration of PA32540 and clopidogrelresults in greater platelet inhibition than synchronousadministration of enteric-coated aspirin andenteric-coated omeprazole and clopidogrelPaul A.Gurbel,MD, a KevinP. Bliden,MBA, a JohnG. Fort,MD, b Young-Hoon Jeong,MD, PhD, a Alan Shuldiner,MD, c

Sumbul Chai, MS, c Tania Gesheff, MSN, a Mark Antonino, MS, a Martin Gesheff, BS, a Ying Zhang, MS, b andUdaya S. Tantry, PhD a Baltimore, MD; and Chapel Hill, NC

Background A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinalcomplications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel,although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administrationof a clopidogrel and a single-tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered asan alternative that might reduce this potential pharmacodynamic interaction.

Methods and Results A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two7-day treatments were separated by 14-day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mgmaintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). Theprimary end point was the inhibition of platelet aggregation (20 μM adenosine diphosphate, maximal extent) after 7 days.CYP2C19 and ABCB1 genotypes were determined.

Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + ECaspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid–induced aggregation. Theeffect of spacing on pharmacodynamics was independent of genotype.

Conclusions PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronouslyadministered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directlyrelevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection.(Am Heart J 2013;165:176-82.)

Current guidelines recommend dual-antiplatelet thera-py (DAPT) with clopidogrel and aspirin for up to 1 year toreduce coronary thrombotic events following percutane-ous coronary intervention (PCI).1 Clopidogrel alone,aspirin alone, and their combination are all associatedwith an increased risk of gastrointestinal (GI) bleeding.2

Proton pump inhibitors (PPIs) are recommended toreduce GI bleeding among patients with a history ofupper GI bleeding, particularly for patients with multiple

From the aSinai Center for Thrombosis Research, Baltimore, MD, bPozen Inc, Chapel HillNC, and cDivision of Endocrinology, Department of Medicine, University of MarylandSchool of Medicine, Baltimore, MD.Clinical Trial Registration: NCT01557335.Submitted April 30, 2012; accepted July 27, 2012.Reprint requests: Paul A.Gurbel,MD, Sinai Center for Thrombosis Research,CardiacCatheterizationLaboratory Sinai Hospital of Baltimore, 2401W Belvedere Ave, Baltimore, MD 21215.E-mail: pgurbel@lifebridgehealth.org0002-8703/$ - see front matter© 2013, Mosby, Inc. All rights reserved.http://dx.doi.org/10.1016/j.ahj.2012.07.032

,

risk factors for GI bleeding who require antiplatelettherapy.2 Clinical guidelines regarding concomitant use ofPPIs and thienopyridines stress balancing overall risks andbenefits, considering both cardiovascular (CV) and GIcomplications.2 At this time, a common regimen forpatients requiring DAPT who are at risk for GI complica-tions is the synchronous administration of enteric-coated(EC) aspirin, EC omeprazole, and clopidogrel.1

The investigational compound PA32540, a combinationtablet consisting of 325 mg aspirin and 40 mg immediate-release omeprazole, was designed to minimize aspirin-related GI toxicity while delivering a bioequivalent doseof aspirin. Because aspirin and clopidogrel are used incombination in routine practice, PA32540 has thepotential for use in combination with clopidogrel. Theconcomitant use of clopidogrel and omeprazole has beenshown to reduce the antiplatelet effects of clopidogrel.3–7

Observational studies and a single randomized clinicaltrial have shown inconsistent effects of concomitant useof thienopyridines and PPIs on CV outcomes.2,8,9

Figure 1

Study Design.

Gurbel et al 177American Heart JournalVolume 165, Number 2

An alternative regimen for patients requiring DAPTwho are at risk for GI complications is a staggeredadministration of clopidogrel and omeprazole. In ahealthy volunteer study, a negative pharmacodynamicinteraction between PA32540 and clopidogrel wasobserved; however, the interaction was reduced byadministering the agents 10 hours apart.4 The latterstudy did not compare 10-hour spacing strategy ofPA32540 and clopidogrel with a common synchronouslyadministered regimen of EC aspirin, EC omeprazole, andclopidogrel. Therefore, the objective of the current studywas to determine whether PA32540 and clopidogrelspaced 10 hours apart would have greater antiplateleteffects than synchronously administered EC aspirin,clopidogrel, and EC omeprazole. In addition, genetictesting was performed to assess the impact of genotypeon the potential interaction.

MethodsStudy designThe current study (Co-Rx) was a randomized, open-label,

single-center, 2-way crossover study in healthy volunteers 40years or older. The study was performed in accordance withstandard ethical principles; written consent was obtained fromall patients. Major exclusion criteria were a history of a bleeding

diathesis or GI bleeding, hemorrhagic stroke, illicit drug oralcohol abuse, coagulopathy, major surgery within 6 weeksbefore randomization, platelet count less than 100,000/mm3,hematocrit less than 25%, creatinine levels below 4 mg/dL,elevated liver enzymes, or current use of nonsteroidal anti-inflammatory drugs, anticoagulants, or antiplatelet drugs.The study design consisted of a screening period and two 7-day

treatment periods with a washout period of at least 14 daysbetween periods (Figure 1). Subjects were screened foreligibility if 20 μM adenosine diphosphate (ADP)–inducedmaximal aggregation (PAmax) was 70% or higher. Subjects (n =30) were then randomly assigned to receive spaced orconcomitant treatment in a crossover fashion as follows:morning dosing of 1 tablet of PA32540 followed 10 hours laterby a 300-mg clopidogrel (Plavix; Sanofi-Aventis US, Bridgewater,NJ) load on day 1 and thenmorning dosing of 1 tablet of PA32540followed 10 hours later by 75mg clopidogrel on days 2 through 7(spaced therapy), or 300 mg clopidogrel + 81 mg EC aspirin + 40mg EC omeprazole (Prilosec; AstraZeneca, Wilmington, DE)dosed synchronously on day 1 and then 75 mg clopidogrel + 81mg EC aspirin + 40 mg EC omeprazole dosed synchronously ondays 2 through 7 (synchronous therapy). Informed consent wasobtained separately for genotyping.

Study drug administration and protocol complianceStudy drug administration was performed only at the research

unit under direct supervision and included an oral assessment toensure that the study drug had been swallowed. Each dose was

178 Gurbel et alAmerican Heart Journal

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administered with 240 mL of water. During synchronoustherapy, clopidogrel was given first, followed immediately byaspirin and then omeprazole. Study subjects were providedbreakfast 1 hour after drug administration and were supervisedin the study unit to ensure compliance. Subjects were explicitlyinstructed by means of a written list not to consume food orliquids containing caffeine during the study. Compliancewas supervised. A safety assessment consisting of vital signs,clinical laboratory analyses, and urinalysis and determination ofadverse events and concomitant medications was completedbefore discharge from the research unit on day 7 of treatmentperiod 2.

Blood and urine samplingAt screening and on days 1 and 7 of each treatment period,

urine was analyzed for cocaine, cannabis, opiates, amphet-amines, barbiturates, and benzodiazepines, using commerciallyavailable assays, and alcohol was determined by breath test. Allfemale subjects of childbearing potential were given a pregnancytest at screening and at check-in on day 1 of each treatmentperiod. A positive test result for alcohol, illicit drugs, orpregnancy excluded the subject from participation in the study.Pretreatment blood samples were collected after overnight

fasting (≥10 hours) and before morning dosing on day 1. On day7, blood samples were collected after an overnight fasting and 1hour after clopidogrel administration. On day 7, during spacedtherapy, blood samples were also collected 1 hour afterclopidogrel administration. Blood was collected from theantecubital vein into Vacutainer tubes (Becton-Dickinson,Franklin Lakes, NJ) after discarding the first 2 to 3 mL of freeflowing blood; the tubes were filled to capacity and gentlyinverted 3 to 5 times to ensure complete mixing of theanticoagulant. Tubes containing 3.2% trisodium citrate wereused for light transmittance aggregometry. Genetic sampleswere collected in an 8.5-mL Vacutainer tube containinganticoagulant citrate dextrose solution A (Becton-Dickinson).

Light transmittance aggregometryThe blood-citrate tubes were centrifuged at 120g for 5

minutes to recover platelet-rich plasma and further centrifugedat 850g for 10 minutes to recover platelet-poor plasma. Theplatelet-rich plasma and platelet-poor plasma were stored atroom temperature to be used within 30 minutes. Plateletaggregation was assessed as described previously.4 Briefly,platelets were stimulated with 5 and 20 μM ADP and 2 mMarachidonic acid (AA). Maximal aggregation was assessedusing a Chronolog Lumi-Aggregometer (Model 490-4D, Haver-ton, PA) with the Aggrolink software package. Measurementsof 20 μM ADP-induced aggregation were performed induplicate. The average of the 2 values represented plateletaggregation at each collection time. Platelet aggregation atbaseline (PA0) was the average of 2 values determined atbaseline. Platelet aggregation at day 7 was the average of 2values collected at day 7 (PA7).

GenotypingGenotyping of the known common loss-of-function

CYP2C19*2 (rs4244285) and ABCB1 C3435T variants(rs045642) was performed using TaqMan SNP genotypingassays (Applied Biosystems, Foster City, CA).10 Sample proces-

sing was completed at the Division of Endocrinology, Diabetesand Nutrition, University of Maryland School of Medicine(Baltimore, MD).

Sample size calculation and statistical analysisThe sample size for this study was calculated using the

statistical software nQuery Advisor version 6.0 (StatisticalSolutions, Saugus, MA). A sample size of 30 subjects in eachtreatment (15 per sequence in a crossover fashion) will haveN90% power to detect a mean difference of 10% inhibition ofplatelet aggregation (IPA) between PA32540 + clopidogreldosed separately and EC aspirin 81 mg + EC omeprazole 40 mg +clopidogrel dosed synchronously using a 2-sample t test at 5% 2-sided significance level, assuming that the mean IPA of PA32540plus clopidogrel dosed separately is 40% and the SD of treatmentdifferences is 14%.The primary end point measure was IPA (20 μM ADP)

defined as (1 − PAmax7/PAmax0) × 100%. The IPA least squaresmeans (LS means) difference between treatments andassociated 95% confidence interval (CI) were calculatedusing analysis of covariance (ANCOVA). The ANCOVA modelincluded sequence, period, and treatment as fixed effects,subjects within sequence as a random effect, and baselineplatelet aggregation as a covariate. The secondary end point isthe IPA calculated using data from 2 mM AA as agonist andwas analyzed using the same methodology as the primary endpoint. The relation of IPA quartiles during synchronousadministration to IPA during spaced administration wasanalyzed using 1-way analysis of variance.

Sources of fundingThe study was supported by POZEN Inc (Chapel Hill, NC).

The authors are solely responsible for the design and conduct ofthis study, all study analyses, the drafting and editing of themanuscript, and its final contents.

ResultsStudy populationThirty predominantly white healthy volunteers with a

mean age of 49 years and a body mass index of 27 kg/m2

were enrolled. Twenty-nine subjects completed bothperiods of the study, whereas 1 subject was unable tocomplete the second period because of adverse events.There were no differences in adverse event occurrencesbetween spaced and synchronous treatments (48% vs53%, respectively). Adverse events included ecchymosis(during spaced-6 events, synchronous-4 events), GI upset(during spaced-3 events, synchronous-6 events), andheadache/dizziness (during spaced-7 events, synchronous-5events). There were no serious adverse events.

Primary analysisThere was no difference in predose ADP-induced

maximum aggregation between treatments (Table I). Atday 7, IPA was greater with spaced PA32540 +clopidogrel therapy vs synchronous EC aspirin + EComeprazole + clopidogrel therapy (least squares [LS]mean difference 7.2%, 95% CI 3%-12%, P = .004) (Table

Table I. Comparison of platelet aggregation on day 1 and 7 between spaced and synchronous administration of clopidogrel

Plateletaggregation (%)

Treatment A (spaced) Treatment B (synchronous) P valuecomparisonat day 7Day 1 Day 7 Day 1 Day 7

2 mM AA (max) 79 (7) 5 (1) 75 (20) 4 (1) .92520 μM ADP (max) 85 (6) 46 (17) 86 (6) 51 (15) .00620 μM ADP (final) 84 (6) 30 (20) 84 (6) 36 (20) .02

Treatment A = PA32540 + clopidogrel (dosed 10 hours apart). Treatment B = EC aspirin 81 mg + EC omeprazole 40 mg + clopidogrel. Data are presented as mean (SD).

Table II. Comparison of mean percent IPA on day 7 betweenspaced and synchronous administration of clopidogrel

Plateletaggregation(IPA %)

TreatmentA (spaced)

Treatment B(synchronous) LS mean

difference(95% CI) PLS mean (SE)

2 mM AA(max)

92 (1) 92 (1) 0.1(−3.3 to 3.4)

.975

20 μM ADP(max)

47 (4) 40 (4) 7.2(2.5 to 11.9)

.004

20 μM ADP(final)

65 (5) 57 (5) 8.2(2.6 to 13.8)

.006

Treatment A = PA32540 + clopidogrel (dosed 10 hours apart). Treatment B = ECaspirin 81 mg + EC omeprazole 40 mg + clopidogrel.

Figure 2

Relation of IPA quartiles during synchronous administration to IPAduring spaced administration.

Gurbel et al 179American Heart JournalVolume 165, Number 2

II). Similar findings based on inhibition of final aggrega-tion were also observed (Table II). At day 7, 20 μM ADP-induced maximal and late final aggregation were lowerduring spaced therapy.

Aspirin effectThere was no difference in predose AA-induced

aggregation between treatments (Table I). Seven-daypostdose AA-induced aggregation was low in bothtreatments (≤5%). Inhibition of platelet aggregation(AA-induced platelet aggregation) did not differ betweentreatments (Table II).

Relation of IPA quartiles during synchronousadministration to IPA during spaced administrationOnly subjects in the lowest IPA quartile during

synchronous administration had significantly greater IPAin response to spaced therapy (Figure 2).CYP2C19 and ABCB1. CYP2C19 loss-of-function

carriers (n = 12, all heterozygotes) had significantlylower IPA compared with wild type (n = 15) during bothdrug administration sequences. There was no influenceof genotype on the pharmacodynamic effect of spacing(Figure 3).ABCB1 C3435T carrier status (CC = 13, CT = 6, and

TT = 8) was not associated with IPA during eithertreatment period (data not shown).

DiscussionThe Co-Rx study demonstrated that a strategy of

PA32540 and clopidogrel spaced 10 hours apart wasassociated with greater antiplatelet effects than a regimenof synchronously administered EC aspirin (81 mg),clopidogrel (75 mg), and EC omeprazole in healthyvolunteers. In this study, there was no difference in thepharmacodynamic effect of spacing between CYP2C19loss-of-function carriers and noncarriers. Subjects withthe lowest platelet inhibition during synchronous admin-istration appeared to benefit most from the spacedadministration strategy of PA32540 and clopidogrel.Many pharmacodynamic studies have been conducted

that assessed the reduced antiplatelet effect of DAPTduring coadministration of PPIs (Table III).3–7 The firstpharmacodynamic study demonstrating reduced plateletinhibition used the vasodilator stimulated phosphoprotein-phosphorylation assay in PCI patients who wererandomly assigned to DAPT with or without synchro-nously administered 20 mg daily EC omeprazole therapy.7

Subsequently, other studies have demonstrated a PPI-clopidogrel pharmacodynamic interactions showing a

Table III. Phamacodynamic studies demonstrating the relation of clopidogrel antiplatelet response to synchronous omeprazole administration

Author(reference) Patients (n) Treatment Method

Results of synchronousomeprazole therapy

Gurbel et al4 Healthy volunteers(n = 30)

Clop (300 mg LD) + EC ASA(325 mg) followed by Clop (75mg) +EC ASA (325 mg) on days 2-7 vsClop (300 mg) + PA32540 followed byClop (75 mg) + PA32540 on days 2-7

Baseline, days 1 and 7: Day 1:LTA (5 and 20 μM ADP),

VASP-PRI, VerifyNow-PRU↓ IPA-5ADP, LSM 4.7 (−1.2 to 10.7);

20ADP, LSM 5.1 (0.3-10.0)↑ VASP-PRI, LSM 5.2

(−0.1 to 10.3)↑ PRU, LSM 9.9 (4.0-15.9)

Day 7:↓ IPA-5ADP, LSM 8.1 (2.5-13.7);

20ADP, LSM 7.3 (1.4-13.2)↑ VASP-PRI, LSM 18.3 (10.7-26.0)↑ PRU, LSM 23.4 (17.9-28.8)

Ferreiro et al5 Healthy volunteers(n = 20)

Clop (600 mg LD/75 mg MD) vsClop (600 mg LD/75 mg MD) +omeprazole (40 mg)

Days 1 and 7: Day 1: no significant differences inPD measuresLTA (5 and 20 μM ADP),

VASP-PRI, VerifyNow-PRUand IPA

Day 7:↓ IPA, (P = .23)↑ VASP-PRI (P = .02)↑ PRU (P = .05) and ↓ IPA (P = .01)

Angiolillo et al6 Healthy volunteers Study 1: Clop (300 mg LD/75 mg MD)vs Clop (300 mg LD/75 mg MD) +omeprazole (80 mg)

Days 1 and 5: Day 1:Study 1:ΔMPA 11.2 (P b .0001),Study 3: ΔMPA 14.7 (P b .0001)

Study 1: (n = 72)

Study 3: Clop (600 mg LD/150 mg MD)vs Clop (600 mg LD/150 mg MD) andomeprazole (80 mg)

MPA (5 ADP), VASP-PRI,PK-Clop H4

Study 1: ΔPRI 17.1 (P b .0001),Study 3: ΔPRI 18.6 (P b .0001)Study 1: ↓ AM 45% (P b .001),Study 3: ↓ 48% (P b .001)

Study 3: (n = 72)

Day 5:Study 1: ΔMPA 8.0 (P b .0001),Study 3: ΔMPA 8.1 (P b .0001)Study 1: ΔPRI 20.7 (P b .0001),Study 3: ΔPRI 19.0 (P b .0001)Study 1: ↓ AM 40% (P b .001),Study 3: ↓ AM 41% (P b .001)

Gilard et al7 Elective PCI(n = 124)

Clop (300 mg LD/75 mg MD) +omeprazole (20 mg MD) or placebofor 7 d. All patients received aspirin(75 mg MD)

Day 7: ↑ PRI: 51.4% ± 16.4% vs 39.8% ±15.4%; P b .0001VASP-PRI

↑ HPR frequency (N50% PRI)60.9% vs 26.7%; P b .001

Clop, Clopidogrel; LD, loading dose; EC ASA, EC aspirin; PA32540 (Pozen, Chapel Hill, NC), novel investigational product composed of 325 mg of EC ASA and 40mg of immediate-release omeprazole; LTA, light transmittance aggregometry; VASP-PRI, vasodilator-stimulated phosphoprotein phosphorylation–platelet reactivity index; LSM, least squares means;PRU, platelet reactivity units; MD, maintenance dose; PD, pharmacodynamic; PK, pharmacokinetic; H4, active metabolite of clopidogrel (exposure of clopi-H4); ΔMPA, change inmaximum platelet aggregation; HPR, high platelet reactivity.

Figure 3

0102030405060708090

100

Spaced Synchronous TreatmentDifference

IPA

(%

)

CYP2C19*2 Carriers (n = 12, het only) CYP2C19*2 Non-Carriers (n = 15)

* *

Influence of CYP2C19*2 carriage on pharmacodynamic effect ofspacing. *P b .01 between carrier statuses.

180 Gurbel et alAmerican Heart Journal

February 2013

reduced antiplatelet effects of clopidogrel in patientsduring synchronous administration of omeprazole.4–6

However, the effects of nonsynchronous administra-tion of clopidogrel and omeprazole have producedconflicting results that may be related to the preparationof omeprazole (Table IV). In one study, concomitanttherapy of delayed-release omeprazole and clopidogrelwas associated with a 50% decrease in the clopidogrelactive metabolite exposure in healthy volunteers andincreased platelet reactivity attributed to the inhibition ofCYP2C19 by omeprazole. In the same study, spacingclopidogrel and delayed-release omeprazole was notassociated with attenuation of the pharmacodynamicinteraction.5 In another study with healthy volunteers,platelet aggregation and the platelet reactivity index weresignificantly increased, and IPA decreased during clopi-dogrel therapy (300 mg load/75 mg daily maintenance)coadministered with EC omeprazole, and this interaction

Table IV. Phamacodynamic studies demonstrating the relation of clopidogrel antiplatelet response to nonsynchronous omeprazole administration

Author(reference) Patients (n) Treatment Method

Results ofnonsynchronous

omeprazole therapy

Gurbel et al4 Healthy volunteers(n = 28)

Clop (300 mg LD) + EC ASA (325 mg)followed by Clop (75 mg) + EC ASA(325 mg) on days 2-7 vs PA32540 inthe AM + Clop (300 mg) 10 h later onday 1 followed by PA32540 in the AM +Clop (75 mg) 10 h later on days 2-7

Baseline, days 1 and 7: Day 1:LTA (5 and 20 μM ADP),VASP-PRI, VerifyNow-PRU

↓ IPA-5ADP, LSM 3.3 (−4.5 to 11.1);↑20ADP, LSM −1.4 (−7.5 to 4.8)↑ VASP-PRI, LSM −3.4 (−8.6 to 1.7)↑ PRU, LSM 6.8 (0.6-13.0)

Day 7:↓ IPA-5ADP, LSM 7.5 (0.9-14.1);

20ADP LSM 4.4 (−0.8 to 9.6)↑ VASP-PRI, LSM 10.1 (3.6-16.7)↑ PRU, LSM 15.9 (9.9-21.8)

Ferreiro et al5 Healthy volunteers(n = 20)

Clop (600 mg LD/75 mg MD) vs Clop(600 mg LD/75 mg MD) in the AM +omeprazole (40 mg) taken 8-12 h later

Days 1 and 7: Day 1: no significant differencesin PD measuresLTA (5 and 20 μM ADP),

VASP-PRI, VerifyNow-PRUand IPA

Day 7:↓ IPA (P = .09)↑ VASP-PRI (P = .001)↑ PRU (P b .01) and ↓ IPA (P b .001)

Angiolillo et al6 Healthy volunteers Study 2: Clop (300 mg LD/75 mg MD)vs Clop (300 mg LD/75 mg MD) andomeprazole (80 mg) administered12 h apart

Days 1 and 5: Day 1:Study 2: ΔMPA 15.9 (P b .0001)Study 2: ΔPRI 19.7 (P b .0001)Study 2: ↓ AM 53% (P b .001)

Study 2: (n = 72) MPA (5 ADP), VASP-PRI,PK-Clop H4

Day 5:Study 2: ΔMPA 5.6 (P = .0014)Study 2: ΔPRI 27.1 (P b .0001)Study 2: ↓ AM 47% (P b .001)

Clop, Clopidogrel; EC ASA, EC aspirin; PA32540 (Pozen), novel investigational product composed of 325 mg of EC ASA and 40 mg of immediate-release omeprazole; H4, activemetabolite of clopidogrel (exposure of clopi-H4); LTA, light transmittance aggregometry; VASP-PRI, vasodilator-stimulated phosphoprotein phosphorylation–platelet reactivity index;LSM, least squares means; PRU, platelet reactivity units; LD, loading dose; MD, maintenance dose; PD, pharmacodynamic; ΔMPA, change in maximum platelet aggregation;PK, pharmacokinetic.

Gurbel et al 181American Heart JournalVolume 165, Number 2

was present irrespective of the timing of an 80-mg dailyomeprazole administration.6 These studies were con-ducted with delayed-release omeprazole and without thebackground of aspirin therapy.The first attempt to characterize the antiplatelet effect

of separate administration of clopidogrel and immediate-release omeprazole with aspirin was the SPACING study,which was a randomized, open-label study of 30 healthysubjects. In the SPACING study, 10-hour delayed admin-istration of clopidogrel (300-mg clopidogrel loading and75-mg maintenance therapy) with 40 mg omeprazolecontained within PA32540 attenuated the pharmacody-namic interaction that was observed during synchronousadministration.4 One possible explanation of the attenu-ated interaction in the SPACING study compared with theinteractions observed in the previous studies is that adose of 40 mg was used rather than the less frequentlyused higher dose of 80 mg omeprazole that was used inother studies.4 Also, the attenuated interaction may berelated to the administration of immediate-release omep-razole formulation of PA32540, which results in peakplasma levels of omeprazole at 32 minutes comparedwith peak plasma levels of 97 minutes that are associatedwith the delayed-release omeprazole.11 The results of theSPACING study concur with those of the current Co-Rx

study, which demonstrated greater inhibition of ADP-induced platelet aggregation with spaced (10 hoursapart) PA32540 and clopidogrel therapy compared withsynchronously administered clopidogrel, EC aspirin, andEC omeprazole.4

One option that has been considered for reducing thepotential interaction between PPIs and clopidogrel is toselect a PPI that demonstrates relatively less influence onthe CYP2C19 enzyme. The relative inhibitory effects ofdifferent PPIs on the CYP2C19 enzyme have been studiedusing pooled human liver microsomes, as well as incryopreserved hepatocytes and recombinant CYP2C19enzyme. Omeprazole and esomeprazole, not R-omepra-zole, lansoprazole, or pantoprazole, were identified asirreversible (or quasi-irreversible) metabolism-dependentinhibitors of CYP2C19.12 However, the results of the Co-Rx study suggest that the influence of the CYP2C19 andABCB1 genotype may not be relevant when clopidogreland PA32540 are administered 10 hours apart.Regarding the clinical relevance of the observed

difference in platelet inhibition (LS mean difference7.2%) in the current study, Matetzky et al13 analyzed therelation of risk of ischemic event occurrence to IPA in asmall post-PCI STEMI population using light transmit-tance aggregometry. In this latter study, the event risk

182 Gurbel et alAmerican Heart Journal

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was greatest in those with the lowest quartile ofinhibition. It is possible that the attenuation of theinteraction induced by spacing PA32540 and clopidogrelin selected patients with baseline high platelet reactivitymay be clinically relevant.

LimitationsThe present study included healthy volunteers 40

years or older; similar findings may not occur in patientswith coronary artery disease. Second, the study did notassess pharmacokinetics, which may have elucidated amechanism for the reduced interaction after spacedtherapy. Also, the antiplatelet response of clopidogrelwas not evaluated for spaced EC formulations ofomeprazole, or with higher doses omeprazole andhigher doses of aspirin. We cannot exclude that amore potent antiplatelet effect is caused by the higheraspirin dose in PA32540.Finally, as with other pharmacodynamics studies, the

potential for interaction was assessed over the shortduration of 1 week. Extrapolation of these data to long-term effects may be highly speculative.

ConclusionsPA32540, which includes a novel immediate-release

formulation of omeprazole, when dosed at least 10 hoursapart from clopidogrel, significantly lessens the pharma-codynamic interaction with clopidogrel compared withthe common regimen of EC aspirin, EC omeprazole, andclopidogrel, and these results were independent ofCYP2C19 and ABCB1 genotypes. Future larger-scalerandomized studies in patients with CV disease managedwith DAPT would be required to determine whether thespaced administration of PA32540 therapy is clinicallysuperior to the use of delayed-release omeprazole.

AcknowledgementsIngrid Witherell, MPH, independent contractor to

Pozen, Inc, provided copyediting assistance for thismanuscript.

DisclosuresDr Paul A Gurbel received research grants, honoraria,

and/or consultancy fees from Pozen, Inc, AstraZeneca,Schering-Plough, Medtronic, Lilly/Sankyo, Sanofi-Aventis,Boston-Scientific, and Bayer. Dr Fort, and Ms Zhang areemployees of POZEN Inc. The remaining authors reportno disclosures.

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