Clinical Therapeutics/Volume 37, Number 3, 2015

Pharmacokinetics and Pharmacodynamics of Ticagrelor and Prasugrel in Healthy Male Korean Volunteers Hae-Sun Jeon, MD1; Mi-Jo Kim, MD, PhD1; Hee-Youn Choi, MD1; Yo-Han Kim, MD1; Eun-Hwa Kim, BS1; A-Reum Kim, MS1; Hyun-Jung Park, BS2; Kyun-Seop Bae, MD, PhD1; and Hyeong-Seok Lim, MD, PhD1 1

Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; and 2Clinical Trial Center, Asan Medical Center, Seoul, Republic of Korea

ABSTRACT Purpose: A combination of clopidogrel and aspirin is the standard treatment for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Two novel antiplatelet agents, ticagrelor and prasugrel, have been shown to rapidly and more effectively inhibit the P2Y12 receptor compared with clopidogrel. The aim of this study was to evaluate and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor and prasugrel in healthy male Korean volunteers. Methods: Two separate studies were conducted. One study was performed by using a single-sequence, open-label, crossover design in 12 volunteers who received a single oral dose of ticagrelor (180 mg) and then a single oral dose of prasugrel (60 mg for 4 volunteers and 30 mg for 8 volunteers) with a 7-day washout period. The other study was a randomized, open-label, parallel-group investigation in which 8 volunteers received a single oral dose of prasugrel (10 mg for 4 volunteers and 30 mg for 4 volunteers). In each study, blood samples for PK and platelet aggregation inhibition analysis were serially collected after the administration of each dose. Plasma concentrations of ticagrelor, AR-C124910XX (the active metabolite of ticagrelor), R-95913 (the inactive metabolite of prasugrel), and R-138727 (the active

Accepted for publication January 19, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.01.010 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

March 2015

metabolite of prasugrel) were measured by using a validated LC-MS/MS method. PK was analyzed by using a noncompartmental method. Maximal platelet aggregations were assessed with light transmission aggregometry after induction with 20 μmol/L of adenosine diphosphate. Findings: Twenty healthy male Korean volunteers participated in the 2 studies. Plasma concentrations of ticagrelor and AR-C124910XX were obtained from 12 subjects, R-95913 from 20 subjects, and R-138727 from 8 subjects. Both ticagrelor and prasugrel were rapidly absorbed, with the shortest median Tmax of 2.0 and 2.25 hours for ticagrelor and AR-C124910XX, respectively, and a Tmax of 0.5 hour for both R-95913 and R-138727. Strong inhibition of platelet aggregation was shown after administration of both ticagrelor and prasugrel, with slightly stronger and more rapid inhibition with prasugrel in the tested doses. Inhibitory activities of prasugrel lasted longer than those of ticagrelor, reflecting the difference in binding kinetics between the 2 drugs. Implications: Prasugrel 30 and 60 mg exhibited slightly stronger, more rapid, and sustainable platelet inhibitory effects compared with ticagrelor 180 mg. These differing effects should be considered when determining the efficacy and adverse effects of ticagrelor and prasugrel. ClinicalTrials.gov identifier:

Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.

563

Clinical Therapeutics NCT01876797 and NCT02075268. (Clin Ther. 2015;37:563–573) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: antiplatelet agents, healthy volunteers, pharmacodynamics, pharmacokinetics, prasugrel, ticagrelor.

INTRODUCTION Thromboembolic disorders, either venous or arterial, are a major health problem worldwide and are associated with mortality and disabilities.1 Because platelets predominate in arterial thrombi compared with venous thrombi, antiplatelet drugs are the mainstay for the prevention and treatment of such disorders.2,3 Antiplatelet therapy is widely used for the treatment of atherosclerotic coronary artery disease. Guidelines formulated by both the American College of Cardiology/American Heart Association and the European Society of Cardiology recommend the use of dual antiplatelet therapy with aspirin in combination with a P2Y12 receptor inhibitor in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI).2,4 These recommendations are primarily based on randomized, Phase III clinical trials of P2Y12 inhibitors such as clopidogrel, prasugrel, and ticagrelor. However, few East Asian patients participated in such trials, especially for the newer agents (eg, ticagrelor, prasugrel), and there is increasing evidence indicating different treatment effects and adverse event profiles between East Asian and white subjects.1 Ticagrelor is an orally administered, non-thienopyridine, cyclopentyltriazolo-pyrimidine that was approved in the European Union in 2010 and in the United States in 2011.5,6 The drug binds reversibly and blocks adenosine diphosphate (ADP) receptors of subtype P2Y12.7 Ticagrelor is an allosteric inhibitor, which binds to a different site than the ADP-binding site. Although ticagrelor possesses pharmacologic activity, it also has a known active metabolite, ARC124910XX, derived from cytochrome P-450 (CYP) 3A4/5 metabolism whose concentration in blood is approximately one third of that of the parent compound.8 It does not require metabolic activation for its therapeutic effect, which may explain its low interpatient variations in drug exposure compared with clopidogrel.9 A previous study found that ticagrelor exerts stronger, faster, and more consistent

564

platelet inhibition compared with clopidogrel in both healthy subjects and in patients with stable coronary artery disease.7 Prasugrel is a third-generation thienopyridine agent that was approved in the European Union, the United States, and in other regions in 2009 for the treatment of ACS in patients undergoing PCI.2 Similar to clopidogrel, prasugrel is a prodrug that is biotransformed into an inactive metabolite (R-95913) and pharmacologically active metabolite (R-138727). R-95913 is formed via hydrolysis, predominantly by intestinal human carboxylesterase 2, whereas CYP2B6, CYP2C9, CYP2C19, and CYP3A4 catalyze the formation process of the R-138727 in the second reaction. R-138727 binds irreversibly to ADP receptors of P2Y12 by forming disulfide bridges between extracellular cysteine residues at positions Cys17 and Cys270 to prevent platelet activation.10 The metabolism of prasugrel into R-138727 is believed to be less affected by genetic variations in CYP2C19 and CYP2C9 compared with clopidogrel and is less affected by drug interactions in CYP3A4 metabolism, leading to less interpatient variations in the level of the active metabolite.11 The aim of the present study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of the newer antiplatelet agents, ticagrelor and prasugrel, in healthy male Korean subjects.

SUBJECTS AND METHODS Subjects Healthy male Korean volunteers between the ages of 19 and 45 years were enrolled in this study. All subjects were in good health, as determined by the results of their medical history, physical examinations, vital signs, routine clinical laboratory tests, and ECGs. Study subjects had a body mass index between 18 and 30 kg/m2 and were negative for HIV, syphilis, and hepatitis B and C virus. They had no history of alcoholism, heavy smoking, or hypersensitivity to Z1 drug. Volunteers who had donated blood within the past 2 months, who had been recipients of a transfusion within the past 1 month, or who had taken any prescription medication within 2 weeks of the start of the study were excluded. All subjects provided written informed consent before participation, and the analyses were conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice

Volume 37 Number 3

H.-S. Jeon et al. and the Declaration of Helsinki. All protocols were approved by the independent institutional review board of Asan Medical Center (Seoul, Republic of Korea).

Study Designs Two separate studies were conducted at Asan Medical Center to examine the PK, PD, safety, and tolerability features of ticagrelor and prasugrel. One arm (study I) was a single-sequence, open-label, crossover study in 12 healthy male volunteers who received a single oral dose of ticagrelor and then a single oral dose of prasugrel with a washout period of 7 days. In that investigation, each subject received a single oral dose of ticagrelor* 180 mg, followed by a single oral dose of prasugrel† 60 mg (n ¼ 4) and 30 mg (n ¼ 8). According to a previous study, the mean t½β of ticagrelor was 8.4 hours and that of AR-C124910XX was 11.5 hours.8 Therefore, the washout period in study I was considered sufficient enough that the ticagrelor administered in period I had no effect on the PK evaluation of prasugrel administered in period II. The second arm (study II) was a randomized, open-label, parallel-group study of 8 healthy male volunteers who received a single oral dose of prasugrel 10 mg (n ¼ 4) and prasugrel 30 mg (n ¼ 4). The recommended loading dose of ticagrelor and prasugrel are 180 and 60 mg, respectively, which was also the standard measurement for the loading dose given to the volunteers. Given that the exposure to the active metabolite of prasugrel and the degree of platelet inhibition are higher in Asian subjects than in white subjects,12–15 the goal of the present study was to examine the PK and PD characteristics in cases of decreased dosage of prasugrel in Korean subjects. All subjects in studies I and II were admitted to the hospital the evening before drug administration (day –1, and day 6 in study I; day –1 in study II) and commenced fasting at 10:00 PM. Subjects took the study drug with 240 mL of water at 9:00 AM. After receiving the drug, subjects were seated on the bed at a 45 degree angle, and no meals were allowed for 4 hours. Lunch and dinner were provided 4 and 9 hours after drug administration, respectively. All subjects were discharged from the clinic on the morning after drug administration. In study I, the subjects repeated the protocol for period II, after the washout period. Trademark: Brilintas (AstraZeneca, Wilmington, Delaware). Trademark: Effients (Eli Lilly and Company, Indianapolis, Indiana).

* †

March 2015

Throughout the entire study, smoking and ingestion of other drugs and beverages containing caffeine were not allowed. Heavy exercise and alcohol consumption were also not permitted. During the admission periods, subjects were only allowed to ingest food and water that had been provided by the clinical trial center.

Blood Sample Collection To conduct PK analyses, blood samples (6 mL) for plasma ticagrelor and AR-C124910XX concentrations were collected into heparinized tubes at 0 (predose) and 10, 15, 25, and 30 minutes and 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours after a single oral dose of ticagrelor. Blood (6-mL samples) was drawn at 0 (predose) and 10, 15, 25, and 30 minutes and 1.5, 2, 2.5, 4, 6, 8, 12, and 24 hours after a single oral dose of prasugrel. Plasma concentrations of R-95913 and both R-95913 and R-138727 were measured for PK analysis of prasugrel in studies I and II, respectively. Blood samples for R-95913 analysis were collected in heparinized tubes, and samples for R-138727 were collected in EDTA tubes; 500 mM of 2-bromo-3'methoxyacetophenone (M815, Tokyo Chemical Industry Co, Ltd, Tokyo, Japan) was then added and mixed with acetonitrile (J.T. Baker Chemical Co, Phillipsburg, New Jersey) to produce R-138727MP.16 All blood samples for PK analysis were drawn via an indwelling intravenous angiocatheter; the first 1 mL of blood was discarded when obtained from the catheter. Plasma was extracted within 30 minutes after collection by centrifugation at 1500g for 15 minutes at 41C and immediately transferred to 1.5-mL tubes (Eppendorf, Hamburg, Germany), which were frozen at –701C.

Analytical Methods Plasma concentrations of ticagrelor and ARC124910XX were determined separately by using a validated LC-MS/MS method after sample preparation by protein precipitation (Clinical Pharmacology Laboratory, Clinical Trial Center of Asan Medical Center). Valsartan was used as an internal standard for both ticagrelor and AR-C124910XX analysis. The sample extracts were analyzed by using HPLC and a Shiseido MG3 μm (2.0  50 mm) column (Shiseido, Tokyo, Japan) under binary gradient mode (the mobile phase consisted of solvent A [water with 0.1% formic acid] and solvent B [acetonitrile with 0.1% formic acid]). The MS system was an API 4000

565

Clinical Therapeutics (ABSciex, Foster City, California) that was operated in positive electrospray ionization mode with multiple reaction monitoring. The calibration curve was linear from 5 to 2000 ng/ mL, and the coefficients of determinations (R2 values) were 40.9981 and 0.9986 for ticagrelor and ARC124910XX, respectively. The lower limit of quantitations (LLOQs) for ticagrelor and AR-C124910XX were set at 5 ng/mL. Using this assay, the intraday accuracy values, as measured in terms of the relative error, ranged from 96.3% to 103.88% for ticagrelor and 98.1% to 106.68% for AR-C124910XX. The intraday precision values, as measured in terms of the %CV, ranged from 2.05% to 7.71% for ticagrelor and 2.52% to 3.77% for AR-C124910XX. The interday accuracy values ranged from 91.44% to 99.23% for ticagrelor and 92.2% to 102.10% for AR-C124910XX. The interday precision values ranged from 4.33% to 6.37% for ticagrelor and 4.71% to 7.10% for AR-C124910XX. Plasma concentrations of R95913 and R138727 after prasugrel administration were measured separately by using a validated LC-MS/MS method following sample preparation by protein precipitation (Clinical Pharmacology Laboratory, Asan Medical Center Clinical Trial Center). AZD6244 was used as the internal standard for both R95913 and R138727 analysis. The sample extracts were analyzed by using HPLC and a Shiseido MG 3 μm (2.0  50 mm) column (Shiseido) under binary gradient mode (the mobile phase consisted of solvent A [water with 5 mM ammonium formate] and solvent B [acetonitrile]). The MS system was an API 4000 (ABSciex) that was operated in positive electrospray ionization mode with multiple reaction monitoring. The calibration curve was linear from 1 to 200 ng/mL and 0.5 to 500 ng/mL, and the R2 values were 40.9981 and 0.9951 for R95913 and R138727, respectively. The LLOQs for R95913 and R138727 were 1 and 0.5 ng/mL, respectively. Using this assay, the intraday accuracy values ranged from 94% to 96.7% for R95913 and 95.08% to 102.40% for R138727. The intraday precision values ranged from 2.60% to 7.52% for R95913 and 3.67% to 9.61% for R138727. The interday accuracy values ranged from 90.47% to 98.04% for R95913 and 89.86% to 98.84% for R138727. The interday precision values ranged from 2.75% to 9.19% for R95913 and 3.41% to 10.44% for R138727.

566

PD Measurements Blood samples for platelet aggregation inhibition analysis were collected in 3.2% sodium citrate Vacutainer tubes (BD Diagnostics, Sparks Glencoe, Maryland) via a indwelling intravenous catheter separate from that of PK sampling. The samples were drawn at 0 (predose), 15, and 30 minutes and at 1, 2, 4, 8, and 24 hours after each dose of ticagrelor; at 0 (predose), 15, and 30 minutes and at 1, 2, 4, 8, and 24 hours (study I); and at 0 (predose), 15, and 30 minutes and at 1, 2, 4, 8, 24, 48, and 72 hours (study II) after each dose of prasugrel. Platelet-rich plasma and plateletpoor plasma (PPP) were obtained by centrifugation of the samples for 10 minutes at room temperature at 200g and 2400g, respectively within 2 hours after collection. Platelet aggregation was measured by using a 2-channel aggregometer (570 VS; Chrono-Log, Havertown, Pennsylvania).17 ADP (20 μmol/L) was used as the inducer of platelet aggregation. Aggregation was measured over 6 minutes in siliconized tubes at 371C while constantly being stirred. Before sample measurement, light transmission was set to 0% for platelet-rich plasma and to 100% for PPP. Platelet aggregation was determined as the maximum percent change in the light transmittance from the baseline percentage obtained by using PPP as a reference, which reflects the maximal platelet aggregations.

Tolerability Assessments To evaluate safety, any subjects who received study medications were closely observed, and adverse events (AEs) were recorded. The regular monitoring and recording of all AEs included any symptoms, their time of onset and disappearance, duration, severity, and relationships with the study drug. Physical examinations and vital signs, including systolic and diastolic blood pressures, were evaluated. Laboratory tests of hematologic, chemical, coagulation, and urine analysis were tested and verified. Resting 12-lead ECG data were also used to evaluate tolerability, heart rate, PR interval, QRS duration, and QT interval. QT intervals were corrected according to heart rate by using the formulas of Bazett and Fridericia, and abnormalities were assessed.

PK and PD Analyses PK analysis was conducted in subjects who completed the total number of scheduled blood samplings.

Volume 37 Number 3

H.-S. Jeon et al. Noncompartmental analysis was performed on the individual plasma concentration–time profiles of ticagrelor, AR-C124910XX, R-95913, and R-138727 by using WinNonlin version 6.3 (Pharsight Corporation, Mountain View, California). For this analysis, plasma concentrations below the LLOQ were substituted with zero. Cmax and Tmax values were determined directly from the observed values. Individual AUC0–last was estimated by linear trapezoidal summation in the ascending period and by log/linear trapezoidal summation in the descending period. AUC0–1 was calculated as the sum of AUC0–last and C0–last/λz, in which C0–last corresponds to the last measured concentration, and λz is the rate constant of the plasma terminal phase calculated by linear regression of the slope of the terminal portion of the log-transformed plasma concentration–time curve.18 The t½β was calculated for each subject as ln(2)/λz. PD analysis was conducted in subjects from the perprotocol set. This set was defined as subjects having completed the study with evaluations of PD criteria after study drug administration and with no relevant deviations interfering with the PD evaluations.

Tolerability Analysis Tolerability analysis was performed in subjects who received at least 1 dose of the study drug. To assess tolerability, several collected parameters, including physical examinations, vital signs, laboratory tests, and 12-lead ECG results, were assessed by using descriptive statistics according to dose. AEs were also included.

Healthy volunteers (n = 12)

Study II

Healthy volunteers (n = 8)

Ticagrelor 180 mg Single oral dose

Randomization

Study I

7-day washout

Prasugrel 10 mg Single oral dose (n = 4) Prasugrel 30 mg Single oral dose (n = 4)

RESULTS Subject Characteristics Of the 20 healthy male subjects enrolled in our 2 separate investigation arms, 12 were included in study I and 8 in study II (Figure 1). All enrolled subjects completed the study with no major protocol violations. The mean age of the 20 subjects was 23.8 years; their mean weight and height were 76.2 kg and 177.0 cm, respectively, and the mean body mass index was 24.2 kg/m2. Demographic data was similar among treatment groups (Table I).

PK Results PK analysis of ticagrelor was based on the respective 168 plasma concentration readings of ticagrelor and ARC124910XX from the 12 subjects in study I; the PK analysis of prasugrel was based on 260 readings of R-95913 (156 from 12 subjects in study I and 104 from 8 subjects in study II) and 104 readings of R-138727 from 8 subjects in study II. In this study, 12 subjects in study I were combined with 8 subjects in study II for evaluation of the PK properties of prasugrel. This combined analysis was believed to be reasonable in that volunteer characteristics were similar, analysis methods were the same in both studies, and the PK data in study I did not differ from those in study II. The plasma drug concentration–time data are displayed in Figure 2, and PK analysis results are summarized in Tables II and III. Prasugrel was absorbed more rapidly than ticagrelor. The median Tmax for R-95913 and R-138727 was  0.5 hour after the drug administration throughout the dosing groups

Prasugrel 60 (n = 4)* or 30 mg (n = 8)* Single oral dose

• Plasma concentration Ticagrelor (n = 168) AR-C124910XX (n = 168) R-95913 (n = 156) • Platelet aggregation (%) Ticagrelor (n = 99) Prasugrel (n = 121) - 60 mg (n = 41) - 30 mg (n = 80)

• Plasma concentration R-95913 (n = 104) R-138727 (n = 104) • Platelet aggregation (%) Prasugrel (n = 80) - 60 mg (n = 40) - 30 mg (n = 40)

Figure 1. Flow diagram for study participation. *The first 4 subjects received prasugrel 60 mg, and the others received prasugrel 30 mg.

March 2015

567

Clinical Therapeutics

Table I. Demographic characteristics. Unless otherwise indicated, values are given as mean (SD). Dosage Regimen

No. of Subjects

Ticagrelor 180 mg Prasugrel 10 mg Prasugrel 30 mg* Prasugrel 60 mg* Total

12 4 12 4 20

23.0 25.3 23.3 23.8 23.8

(2.6) (5.7) (3.9) (3.8) (4.1)

Body Mass Index, kg/m2

Weight, kg

Height, cm

77.4 (10.6) 70.5 (7.3) 75.7 (7.6) 83.3 (13.4) 76.2 (9.4)

179.2 (5.4) 170.9 (4.0) 177.4 (3.9) 182.1 (7.2) 177.0 (5.8)

24.0 24.1 24.0 25.1 24.2

(2.5) (1.8) (1.8) (3.4) (2.1)

Four subjects treated with prasugrel 60 mg and 8 of 12 subjects treated with prasugrel 30 mg also received ticagrelor 180 mg in study I with a crossover design.

in this study, and those of ticagrelor and ARC124910XX were 2.0 and 2.25 hours, respectively. Mean t½β values were longer for ticagrelor (8.1 hours) and AR-C124910XX (11.6 hours) than for R-95913 (2.5–7.1 hours) and R-138727 (2.7–8.3 hours). However, the t½β of R-95913 and R-138727 tended to increase with higher doses.

1000 800 600

1400 1200 1000 800 600 400 200 0

400

0

2

4

3

5

6

Time After Dose (h)

200 0 0

4

8 12 16 Time After Dose (h)

C

20

400 300 200 100

300 200 100 0 0.0

0.5 1.0 1.5 Time After Dose (h)

2.0

0 0

4

8 12 16 Time After Dose (h)

20

160 140 120 100 80 60 40

24

180 160 140 120 100 80 60 40 20 0 0.0

0.5 1.0 1.5 Time After Dose (h)

20

2.0

0 0

D

400

R-95913 (n = 4) R-138727 (n = 4)

180

24

R-95913 (n = 12) R-138727 (n = 4) Plasma Concentration (ng/mL)

Plasma Concentration (ng/mL)

1

Plasma Concentration (ng/mL)

1200

B

Plasma Concentration (ng/mL)

Plasma Concentration (ng/mL)

Plasma Concentration (ng/mL)

1400

Both drugs exhibited strong inhibitory effects on platelet aggregation (Table IV, Figure 3). A single oral dose of ticagrelor (180 mg) induced a maximum inhibition of 85% at an average of 2 hours after dosing. Prasugrel inhibited platelet aggregation in a dose-dependent manner, with a maximum 61.7%

Plasma Concentration (ng/mL)

Ticagrelor (n = 12) AR-C124910XX (n = 12)

A

PD Results

4

8 12 16 Time After Dose (h)

20

24

R-95913 (n = 4)

400 Plasma Concentration (ng/mL)

*

Age, y

300

200

100

400 300 200 100 0 0.0

0.5 1.0 1.5 Time After Dose (h)

2.0

0 0

4

8 12 16 Time After Dose (h)

20

24

Figure 2. Mean (SD) plasma drug concentration over time of ticagrelor and prasugrel. A, ticagrelor 180 mg; B, prasugrel 10 mg; C, prasugrel 30 mg; and D, prasugrel 60 mg.

568

Volume 37 Number 3

H.-S. Jeon et al.

Table II. Pharmacokinetic results for ticagrelor. Values are given as mean (SD) or median (range). Ticagrelor 180 mg Parameter Cmax, ng/mL Tmax, h AUC0–last, ng ∙ h/mL AUC0–1, ng ∙ h/mL CL/F, L/h Vz/F, L t½β, h

Ticagrelor (n ¼ 12) 1013.1 2.0 5659.8 6367.1 31.2 348.5 8.1

(277.2) (1.0–4.0) (1800.0) (2353.0) (9.2) (71.4) (1.6)

AR-C124910XX (n ¼ 12) 284.6 2.25 2088.81 2681.41 69.6 1138.6 11.6

(47.3) (2.0–4.0) (337.2) (542.1) (13.6) (171.1) (2.1)

Vz ¼ volume of distribution during the terminal phase; F ¼ bioavailability.

inhibition at 10 mg, 94.7% at 30 mg, and 99.4% at 60 mg at 4 hours after dosing. Although the inhibitory effect was more rapid with ticagrelor, the effect was more sustainable after prasugrel administration.

Tolerability Tolerability was assessed for all 20 subjects who received study medications. One patient reported bruising on the right leg 5 days after administration of prasugrel 30 mg in study I. This AE was mild in severity and was believed to be related to the study drug. The subject recovered fully without any additional treatment. No clinically significant changes or differences between the treatment groups were observed over time in terms of physical examinations, vital signs, laboratory tests, and 12-lead ECG results.

DISCUSSION More than a decade after the introduction of dual antiplatelet therapy as the standard of care in the setting of ACS and PCI,19,20 the domination of the market by clopidogrel has come to an end. The advent of new antiplatelet agents was the result of clopidogrel having several drawbacks, including delayed onset of action, considerable interindividual variability in platelet responses, genetic polymorphisms affecting its metabolism, drug–drug interactions, and the 2-step activation process catalyzed by a series of CYP isozymes.21–23 Ticagrelor and prasugrel, the newer antiplatelet agents, determine a faster, greater, and more consistent ADP receptor inhibition than

March 2015

clopidogrel, with a near complete inhibition of platelet aggregation between 1 and 2 hours after administration of an oral loading dose.24,25 The present study directly compared the PK and PD characteristics of ticagrelor and prasugrel in healthy male Korean volunteers. Both ticagrelor (180 mg) and prasugrel (10, 30, and 60 mg) were rapidly absorbed after single oral doses, with a shorter Tmax seen for prasugrel (0.5 hour) compared with ticagrelor (2 hours). Loading doses of ticagrelor (180 mg) and prasugrel (60 mg) caused near complete inhibition of platelet aggregation (IPA) induced by 20 μM of ADP, with slightly higher maximal inhibition with prasugrel. Despite slower absorption of ticagrelor as shown by the longer Tmax, ticagrelor demonstrated faster onset of IPA (shorter time to maximum IPA) than prasugrel. This could result from the different association/dissociation binding kinetics to the target between ticagrelor and prasugrel. IPA was sustained for a longer period after prasugrel, reflecting its irreversible binding to the P2Y12 receptor and its inhibitory effect on platelet survival. IPA after ticagrelor decreased more rapidly with declining plasma concentrations, supporting the BID dosing regimen over the once-daily regimen as used in prasugrel.26 However, ticagrelor-associated IPA declined more slowly than the declining rate of plasma concentration of ticagrelor or AR-C124910XX, which may indicate the slowly reversible binding nature of ticagrelor.27 Prasugrel exhibited dose-dependent IPA at 10 to 60 mg, and the duration of prasugrel-induced IPA differed between doses.

569

Clinical Therapeutics

Table III. Pharmacokinetic results for prasugrel. Values are given as mean (SD) or median (range). Prasugrel 10 mg Parameter

R-95913 (n ¼ 4)

Cmax, ng/mL Tmax, h AUC0–last, ng ∙ h/mL AUC0–1, ng ∙ h/mL CL/F, L/h Vz/F, L t½β, h

40.58 0.46 55.6 60.48 226.4 704.7 2.5

(18.12) (0.42–1.0) (35.1) (36.6) (142.2) (302.1) (0.9)

Cmax, ng/mL Tmax, h AUC0–last, ng ∙ h/mL AUC0–1, ng ∙ h/mL CL/F, L/h Vz/F, L t½β, h

R-95913 85.6 0.5 137.0 148.8 226.0 1386.2 4.5

(n ¼ 12) (39.6) (0.17–1.0) (54.9) (57.2) (72.6) (400.2) (1.4)

R-138727 (n ¼ 4) 115.7 0.5 110.8 113.3 90.9 346.8 2.7

(61.9) (0.42–1.0) (22.8) (22.8) (17.1) (194.4) (1.6)

R-138727 355.2 0.5 334.7 342.7 90.4 1085.7 8.3

(n ¼ 4) (136.3 (0.25–1.0) (74.7) (75.2) (17.2) (304.5) (1.8)

Prasugrel 30 mg

Prasugrel 60 mg Cmax, ng/mL Tmax, h AUC0–last, ng ∙ h/mL AUC0–1, ng ∙ h/mL CL/F, L/h Vz/F, L t½β, h

R-95913 236.2 0.5 283.3 298.4 226.4 704.7 7.1

(n ¼ 4) (128.7) (0.43–0.52) (113.2) (118.4) (142.2) (302.1) (2.9)

R-138727 NA NA NA NA NA NA NA

Vz ¼ volume of distribution during the terminal phase; F ¼ bioavailability; NA ¼ not applicable.

The Tmax of ticagrelor and AR-C12490XX after administration of 180 mg of ticagrelor is reportedly 1.5 to 3 hours,8,28 which is similar to our current findings of Tmax values of 1 to 4 hours for ticagrelor and 2 to 4 hours for AR-C12490XX. In this study, the mean IPA values were 85.0%, 84.1%, and 58.9%, respectively, at 2, 4, and 24 hours after administration of ticagrelor 180 mg. The IPA change caused by administration of ticagrelor in the healthy male Korean subjects of our study is similar to that reported previously in white subjects,26 although a direct comparison between these ethnic groups was not strictly feasible. Our study results regarding ticagrelor also agree with those of a previous report showing no

570

ethnic differences between Chinese and whites subjects in terms of the PK and PD findings of ticagrelor.29 Several studies have suggested that the exposure to the active metabolite of prasugrel and the degree of platelet inhibition are higher in Asian subjects than those in white subjects.12–15 The lower mean body weight of Asian subjects compared with white subjects may contribute to the higher exposure of prasugrel’s active metabolite in Asian subjects.14,15 Variations in CYP2C19 and CYP2C9 genetics cannot explain the higher active metabolite exposure in Asian subjects because CYP2C19 and CYP2C9 genotypes associated with reduced function do not seem to affect the prasugrel PK or PD response.30 In our study, after

Volume 37 Number 3

H.-S. Jeon et al.

Table IV. Inhibition of platelet aggregation (%) over time. Values are given as mean (SD). Ticagrelor 180 mg (n ¼ 11)

Time, h 0 0.25 0.5 1 2 4 8 24 48 72

Prasugrel 10 mg (n ¼ 4)

100 (0) 10.2 (14.7) 52.6 (29.0) 77.7 (13.2) 85.0 (9.4)* 84.1 (8.8) 81.5 (10.8) 58.9 (13.0) NA NA

100 6.9 16.4 34.7 46.5 61.7 46.1 30.1 34.9 37.6

Prasugrel 30 mg (n ¼ 12)

(0) (4.7) (16.6) (17.0) (28.5) (12.8)* (29.2) (20.5) (26.3) (19.5)

100 12.9 58.6 88.7 94.1 94.7 94.5 83.8 72.0 66.1

(0) (26.3) (23.0) (9.8) (7.5) (5.3)* (6.5) (9.6) (8.1)† (18.0)†

Prasugrel 60 mg (n ¼ 4) 100 (0) 38.3 (25.9) 92.2 (5.6) 98.5 (2.3) 97.0 (4.5) 99.4 (0.7)* 97.8 (1.9) 99.7 (0.6) NA NA

NA ¼ not applicable. * Maximum inhibition of platelet aggregation. † Eleven subjects.

administration of 30 and 60 mg of prasugrel, the IPA increased substantively to a mean IPA of 88.7% and 98.5% at 1 hour, respectively, which is also similar to the results of a previous study13,14. To the best of our knowledge, no large-scale clinical trials have yet been conducted comparing the treatment effectiveness and safety of ticagrelor and prasugrel. The PK and PD characteristics explored in the present trials should be considered when assessing the efficacy and safety of these drugs. Further evaluations on the newer antiplatelet agents in patients are needed.

A

Single oral doses of ticagrelor (180 mg) and prasugrel (10, 30, and 60 mg) were tolerable in these healthy male Korean subjects. Direct comparisons and quantitative PK and PD data for ticagrelor and prasugrel indicate that although prasugrel is absorbed more rapidly, the onset of pharmacologic effect is faster after ticagrelor administration, and the extent and duration of platelet inhibition are stronger and more prolonged with prasugrel compared with ticagrelor. These results provide valuable insights into the efficacy and safety of ticagrelor and prasugrel for patient treatment.

B IPA on Ticagrelor, 180 mg (n = 12)

100

80

60

60

40 20

IPA on Prasugrel, 10 mg (n = 4) IPA on Prasugrel, 30 mg (n = 12) IPA on Prasugrel, 60 mg (n = 4)

100

80 IPA (%)

IPA (%)

CONCLUSIONS

40 20

0

0 0

4

8

12

16

Time After Dose (h)

20

24

0

8

16 24 32 40 48 56 64 72 Time After Dose (h)

Figure 3. Inhibition of platelet aggregation (IPA) over time on ticagrelor and prasugrel. A, ticagrelor; B, prasugrel.

March 2015

571

Clinical Therapeutics

ACKNOWLEDGMENTS The authors acknowledge the clinical trial center at Asan Medical Center for contributions to protocol development, study conduction, and manuscript review. All authors agree with the content of the manuscript. The corresponding author made the final decision regarding its submission. The authors also acknowledge all the subjects, study coordinators, staff, and nurses at Asan Medical Center; without their help, this study would not have been possible. Drs. Jeon, M.-J. Kim, and Lim contributed equally to this work. Protocol development was performed by Drs. Jeon, M.-J. Kim, Choi, Y.-H. Kim, Bae, and Lim. Assay development for ticagrelor and prasugrel was conducted by Mrs. Park, Ms. A.-R. Kim, and Ms. E.-H. Kim. Subject recruitment and data collection were performed by Drs. Jeon, M.-J. Kim, Choi, and Y.-H. Kim. Drs. Jeon, M.-J. Kim, and Lim contributed to the review of the data analyses, literature search, figure/table creation, and manuscript writing. Manuscript revisions were performed by all authors.

5. 6. 7.

8.

9.

10.

11.

CONFLICTS OF INTEREST This study was supported by a grant of the Korea Health Industry Development Institute R&D Project, Ministry for Health & Welfare, Republic of Korea. The authors have indicated that they have no other conflicts of interest regarding the content of this article. There was no sponsor in these clinical trials. These were investigator initiated trials.

12.

13.

REFERENCES 1. Levine GN, Jeong YH, Goto S, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol. 2014;11: 597–606. 2. Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:776s– 814s. 3. Goodman SG, Menon V, Cannon CP, et al. Acute STsegment elevation myocardial infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:708s–775s. 4. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/ AHA/SCAI guideline for percutaneous coronary intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association

572

14.

15.

16.

17.

18.

Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2012;79:453–495. European public assessment report (EPAR) for Brilique. European Medicines Agency. 2010. FDA. approves blood-thinning drug Brilinta to treat acute coronary syndromes. US Food and Drug Administration. 2011. Guo LZ, Kim MH, Jin CD, et al. Comparison of pharmacodynamics between low dose ticagrelor and clopidogrel after loading and maintenance doses in healthy Korean subjects. Platelets. 2014:1–7. Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010;38:1514–1521. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet. 2010;3:556–566. Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesth Analg. 2011;112:292–318. Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos. 2006;34:600–607. Small DS, Kothare P, Yuen E, et al. The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects. Eur J Clin Pharmacol. 2010;66: 127–135. Kim MH, Zhang HZ, Jung DK. Pharmacodynamic comparisons for single loading doses of prasugrel (30 mg) and clopidogrel (600 mg) in healthy Korean volunteers. Circ J. 2013;77:1253–1259. Yu KS, Park KW, Kelly RP, et al. Pharmacokinetic and pharmacodynamic effects of prasugrel in healthy Korean males. J Cardiovasc Pharmacol. 2013;62:72–77. Cui YM, Wang ZN, Chen XW, et al. Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects. Acta Pharmacol Sin. 2012;33:1395–1400. Farid NA, McIntosh M, Garofolo F, et al. Determination of the active and inactive metabolites of prasugrel in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2007;21:169–179. Guha S, Mookerjee S, Lahiri P, et al. A study of platelet aggregation in patients with acute myocardial infarction at presentation and after 48 hrs of initiating standard anti platelet therapy. Indian Heart J. 2011;63:409–413. Rowland M, Tozer T. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

Volume 37 Number 3

H.-S. Jeon et al. 19. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502. 20. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by longterm therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001; 358:527–533. 21. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/ AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2009;54:2205–2241. 22. Combescure C, Fontana P, Mallouk N, et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost. 2010;8:923–933. 23. Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Cardiol. 2010;56:919–933. 24. Jakubowski JA, Winters KJ, Naganuma H, Wallentin L. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev. 2007;25:357–374. 25. Ferri N, Corsini A, Bellosta S. Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. Drugs. 2013;73:1681–1709. 26. Butler K, Pharmacokinetics Teng R. pharmacodynamics, safety and tolerability of multiple ascending doses of

March 2015

ticagrelor in healthy volunteers. Br J Clin Pharmacol. 2010;70:65–77. 27. Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014;34:1077–1090. 28. Teng R, Pharmacokinetics Butler K. pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol. 2010;66:487–496.

29. Li H, Butler K, Yang L, et al. Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese subjects: an open-label, sequential, two-cohort, single-centre study. Clin Drug Investig. 2012;32:87–97. 30. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphism of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5:2429–2436.

Address correspondence to: Hyeong-Seok Lim, MD, PhD, Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. E-mail: [email protected]

573