Pharmacokinetic Profiles of Ticagrelor Orodispersible Tablets in Healthy Western and Japanese Subjects.

BACKGROUND AND OBJECTIVES: Ticagrelor is an antiplatelet agent for patients with acute coronary syndrome or a history of myocardial infarction. Two studies compared pharmacokinetic profiles of orodispersible (OD) ticagrelor tablets versus immediate-release (IR) tablets in Western and Japanese subjects.
METHODS: Both studies were open-label, randomized, crossover, single-center trials. Thirty-six healthy subjects (94% white, 6% other race; Western study NCT02400333) and 42 Japanese healthy subjects (Japanese study NCT02436577) received a single 90-mg ticagrelor dose as an OD tablet [with/without water, and via a nasogastric tube (Western study only)], and an IR tablet; washout between treatments was ≥7 days. Assessments included ticagrelor and AR-C124910XX (active metabolite) plasma concentrations for pharmacokinetic analyses, and safety evaluations.
RESULTS: In the Western study, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for ticagrelor and AR-C124910XX maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC) were within the acceptance interval (80%-125%) for OD tablets (with/without water, via a nasogastric tube) versus the IR tablet; except for an ~15% lowering of ticagrelor C max (90% CI: 76.77%-93.78%) for the OD tablet taken with water. In the Japanese study, 90% CIs of the GMRs for AUC and C max of both ticagrelor and AR-C124910XX were all within the acceptance intervals for the OD (with/without water) versus IR tablet. No new safety issues were identified.
CONCLUSIONS: Ticagrelor administered as an OD tablet to Western (without water, and via a nasogastric tube) and Japanese (with/without water) subjects was bioequivalent to the IR tablet.

RCT Entities:   Population Interventions Outcomes

Key Points

Introduction

Ticagrelor is an orally administered, direct-acting, reversibly binding P2Y12 receptor antagonist. The mechanism of action of ticagrelor involves the inhibition of ADP-induced platelet aggregation [1-3], and the inhibition of the equilibrative nucleoside transporter 1, thereby reducing adenosine cellular uptake [3, 4].

In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) plus aspirin significantly reduced the rate of the primary composite endpoint [myocardial infarction (MI)/stroke/death from vascular causes] in patients with acute coronary syndrome (ACS) versus clopidogrel (300–600 mg loading dose, 75 mg once daily thereafter) plus aspirin, with no difference in the overall rate of major bleeding [5]. In the prospective Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) study, patients with a prior MI (1–3 years previously) received either ticagrelor (60 or 90 mg twice daily) or placebo and low-dose aspirin [6]. Findings from the PEGASUS-TIMI 54 study showed that long-term therapy (median follow-up 33 months) with ticagrelor significantly reduced the risk of MI/stroke/death from vascular causes versus placebo [6]. Rates of TIMI major bleeding were higher with ticagrelor versus placebo, although similar rates of intracranial hemorrhage or fatal bleeding were seen across the groups [6]. Based on results of the PLATO and PEGASUS-TIMI 54 studies, ticagrelor is approved to reduce the rate of cardiovascular death, MI, and stroke in patients with ACS (180 mg loading dose, then 90 mg twice daily together with low-dose aspirin for the first year after the ACS event) or a history of MI (60 mg twice daily together with low-dose aspirin from 1 year after the ACS event) [7]. Ticagrelor is recommended in several major US and EU guidelines as an antiplatelet therapy for patients with ST-elevation ACS [8, 9] or non-ST elevation ACS [10, 11].

Oral ticagrelor is rapidly absorbed and has a linear pharmacokinetic (PK) profile [12, 13], and the major, active metabolite is AR-C124910XX [3, 14, 15]. Plasma concentrations of AR-C124910XX are approximately 30%–40% of ticagrelor plasma concentrations [3]. Both ticagrelor and AR-C124910XX are reversible P2Y12 receptor antagonists, and AR-C124910XX has a similar potency to ticagrelor in inhibiting the P2Y12 receptor [3]. The main pharmacodynamic effect, platelet inhibition, is rapid, temporary, and related to plasma concentrations of both ticagrelor and AR-C124910XX [3, 12, 13, 16, 17]. In Asian subjects, mean bioavailability of ticagrelor and AR-C124910XX is ~40% higher versus Caucasian subjects [18-21]. However, in the Asia (n = 1056) and China (n = 383) subgroups of the PLATO study, the efficacy and safety of ticagrelor versus clopidogrel were generally consistent with the overall study population [5]. In the Phase Three International study of Ticagrelor and Clinical Outcomes in Asian ACS patients (PHILO) study in Japanese, Korean and Taiwanese patients with ACS, treatment with standard doses of ticagrelor resulted in higher event rates of the primary safety and efficacy endpoints versus clopidogrel, the differences between the groups were not statistically significant [22].

Certain patients who cannot take standard tablets require alternative formulations [23], e.g. unconscious, intubated patients, those with certain co-morbidities, critically ill patients (e.g. 15% of survivors of critical illness, 51% of cardiac surgery patients on mechanical ventilation >48 h [24] have swallowing difficulties), and the elderly (e.g. 15%–20% of the elderly population in the USA [25]). Furthermore, dysphagia, a common problem in adults (~4% incidence in the USA [26]), may result in drug administration errors [27]. Such patients who are unable to take tablets encompass those with cardiovascular disease [28-31] who may need antiplatelet therapy.

It is well recognized that drug formulations impact pharmacokinetic parameters [32]. For ticagrelor, bioequivalence was demonstrated for crushed versus whole tablets in healthy subjects [33]. The ticagrelor prescribing information notes that crushed ticagrelor tablets can be used for patients with swallowing difficulties [7]. However, crushing tablets is often inconvenient and requires access to water. An orodispersible (OD) tablet would overcome these issues, and would be suitable for patients with swallowing difficulties and who are unable to swallow whole tablets. OD tablets differ from traditional tablets as they are designed to dissolve or disintegrate on the tongue rather than being swallowed whole [34, 35]. Several different processes, such as freeze-drying, cotton-candy process, spray drying, mass extrusion and compaction, are available for preparing OD tablets that rapidly disintegrate in the mouth [35]. In addition, excipients to aid the feel of the OD tablet in the mouth also contribute to disintegration [35]. Other advantages of OD tablets include convenience of dosing and improved patient compliance [34]. Given that OD tablets offer several advantages for patients with swallowing difficulties, and have the convenience of a tablet that can be taken without water, such formulations have an important role in oral drug delivery [34, 35].

Given the clinical need for a ticagrelor formulation suitable for patients unable or unwilling to swallow tablets, an OD 90-mg tablet formulation of ticagrelor has been developed (Fig. 1). Compared with the immediate-release (IR) tablet, the ticagrelor OD tablet contains excipients to aid disintegration on the tongue and to give a smooth feeling in the mouth, which facilitates swallowing of the dispersed tablet. Also, the OD tablet is non-coated and has a more porous structure that facilitates water ingress to further enhance rapid disintegration.

Fig. 1

Ticagrelor OD tablet (white) and IR tablet (yellow). IR immediate release, OD orodispersible

Two studies in healthy subjects were conducted with ticagrelor OD tablets. One study recruited mainly white, healthy subjects (referred to as the Western study herein) and the other study was in Japanese, healthy subjects. Both studies assessed the pharmacokinetic profiles of ticagrelor OD tablets versus the currently approved formulation of IR tablets.

Methods

Study Designs and Treatments

The Western study was an open-label, randomized, four-period, four-treatment, crossover, single-center, single-dose study (NCT02400333) (Fig. 2a). The Japanese study was an open-label, randomized, three-period, three-treatment, crossover, single-center, single-dose study (NCT02436577) (Fig 2b).

Fig. 2

Flow chart showing the treatment sequences and periods for the a Western study, and b Japanese study. Treatment A = a single 90-mg ticagrelor OD tablet administered with water; Treatment B = a single 90-mg ticagrelor OD tablet administered without water; Treatment C (Western study) = a single 90-mg ticagrelor OD tablet suspended in water administered via a nasogastric tube with water; Treatment C (Japanese study)/Treatment D (Western study) = a single 90-mg ticagrelor IR tablet administered with water. IR immediate release, OD orodispersible

In both studies, subjects were randomized to a treatment sequence on day 1 of the first treatment period; the Western study had four treatment sequences (Fig. 2a) and the Japanese study had six treatment sequences (Fig. 2b). Randomization codes were assigned strictly sequentially as the subjects became eligible. For each treatment period, ticagrelor was administered on day 1 after an overnight fast. The three treatments that were used in both studies were: a single 90-mg ticagrelor OD tablet administered with water (the OD tablet was placed on the tongue to disintegrate then swallowed with noncarbonated water at room temperature); a single 90-mg ticagrelor OD tablet administered without water (the OD tablet was disintegrated on the tongue then swallowed with saliva); and a single 90-mg ticagrelor IR tablet administered with water. In the Western study only, a single 90-mg ticagrelor OD tablet suspended in water was administered via a nasogastric tube with water. The total volume of water used to administer ticagrelor was 200 mL (Western study) or 150 mL (Japanese study). The washout period between treatments in each study was at least 7 days.

Study Populations

For both studies, healthy men and women (non-pregnant, not lactating, post-menopausal or surgically sterile) were eligible for inclusion. Japanese subjects were defined as those who had both parents and four grandparents who were Japanese. For the Western subjects, the age and body mass index (BMI) ranges were 18–55 years and 18.5–29.9 kg/m2, respectively. For the Japanese subjects, the age and BMI ranges were 20–45 years and 18.0–27.0 kg/m2, respectively. The minimum and maximum body weight permitted were ≥50 to ≤100 kg (Western subjects) and ≥45 to ≤85 kg (Japanese subjects).

In both studies, subjects were excluded for the following key reasons: a history or presence of any condition known to interfere with drug absorption, distribution, metabolism or excretion; a known or suspected history of alcohol and/or drug abuse; plasma or blood donation or blood loss >500 mL during the 3 months prior to screening; use of any drug or presence/history of any condition known to increase the propensity for bleeding for 2 weeks before randomization; platelet count <150 × 109/L; current smokers; previous smoking or nicotine patch use in the previous 3 months; and use of enzyme inducers within the previous 3 weeks.

Study Assessments

Pharmacokinetics

In both studies, 2 mL blood samples were collected at 0 (pre-dose), and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 h after each treatment dose. Harvested plasma samples were stored at ≤−20 °C until analysis.

Plasma concentrations of ticagrelor and AR-C124910XX were analyzed using a fully validated, liquid chromatography–tandem mass spectrometry method [36]. The range of the calibration curves for ticagrelor and AR-C124910XX were 5–5000 ng/mL and 2.5–2500 ng/mL, respectively. The mean intra-batch precision and accuracy of this method is 4.0%–8.4% and 91.9%–109.0%, respectively, for ticagrelor, and 5.2%–16.9% and 86.8%–109.2%, respectively, for AR-C124910XX [36].

Safety and Tolerability

Adverse events (AEs) were recorded continuously throughout both studies (for further details, see Supplementary methods). At screening and follow-up, all subjects had a physical examination, a vital signs check (blood pressure and pulse), a 12-lead electrocardiogram, and an evaluation of clinical laboratory parameters [hematology, clinical chemistry, and urinalysis (dipstick)]. Vital signs were also assessed during each treatment period at pre-dose (0 h) and post-dose at 2, 4, and 24 h.

Data Analyses

Sample Sizes

Based on the results of a previous ticagrelor study (drug–drug interaction with diltiazem [37]), the within-subject coefficient of variations for maximum plasma concentration (C max), the area under the plasma–concentration time curve (AUC) from zero to infinity (AUC0–∞) for ticagrelor and AR-C124910XX were assumed to be ≤24% for both compounds. To achieve a statistical power of 90% that a two-sided 90% confidence interval (CI) for the ratio of C max between two different ticagrelor treatments would be contained within the 0.80–1.25 limit, 28 (using a four-sequence Williams design for four periods and four treatments) and 30 (using a six-sequence Williams design for three periods and three treatments) evaluable subjects would be required in the Western and Japanese studies, respectively. To allow for withdrawals, two subjects were added to each sequence. Thus, up to 36 and 42 subjects were randomized in the Western and Japanese studies, respectively.

Pharmacokinetic Analyses

Ticagrelor and AR-C124910XX pharmacokinetic parameters were calculated using standard non-compartmental methods (WinNonlin® Professional, Pharsight Corporation, Mountain View, CA, USA). Key pharmacokinetic parameters were: AUC0–∞; AUC0–t; C max; time to C max (t max); terminal half-life (t ½); and metabolite:parent ratios of C max, AUC0–∞, and AUC0–t. Pharmacokinetic data were summarized by treatment group using descriptive statistics.

Within each study, statistical comparisons between the OD tablet, for each administration route, and the IR tablet (reference) were performed on the difference of log-transformed C max, AUC0–∞, and AUC0–t of both ticagrelor and AR-C124910XX. An analysis of variance model including fixed effects for treatment, sequence, period and subject within sequence was used to estimate the treatment differences with 90% CIs. The estimates were back transformed to obtain the geometric mean ratios (GMRs) for each pair of treatments. The criteria for acceptance was for the 90% CIs of the GMRs to be within 80%–125% [38-40].

Results

Subjects

Western Study

Thirty-six healthy subjects were randomized. Four subjects were withdrawn due to protocol deviations and two subjects withdrew consent. Thus, 30 subjects completed all four treatment periods. Overall, of the randomized subjects, 32 (89%) were male, and 34 (94%) were white and 2 (6%) were of another race. The mean ± standard deviation (SD) age and BMI were 42 ± 12 years and 24.6 ± 2.4 kg/m2, respectively.

Japanese Study

Forty-two Japanese healthy subjects were randomized and one was withdrawn due to a protocol deviation. Thus, 41 subjects completed all three treatment periods. All randomized subjects were male, and the mean ± SD age and BMI were 31 ± 7 years and 21.8 ± 2.0 kg/m2, respectively.

Pharmacokinetics

Plasma concentration–time curves for ticagrelor (Fig. 3a) and AR-C124910XX (Fig. 3b) following administration of an OD tablet with or without water, or administered via a nasogastric tube were generally similar to those following administration of an IR tablet.

Fig. 3

Arithmetic mean (± SD) plasma concentrations of a ticagrelor and b AR-C12491XX over time following administration of a 90-mg dose of ticagrelor as an OD tablet (with and without water; suspended in water administered via a nasogastric tube), or an IR tablet to Western healthy subjects. IR immediate release, NG nasogastric, OD orodispersible, SD standard deviation

With the OD tablet (regardless of administration method) and the IR tablet, ticagrelor was rapidly absorbed with a median t max of ~2 h, and the mean t ½ was ~8 h. AR-C124910XX was rapidly formed with a median t max of 2–3 h, and the mean t ½ was ~9 h (Table 1).

Table 1

Pharmacokinetic parameters and statistical analyses of ticagrelor and AR-C124910XX following administration of a 90-mg dose of ticagrelor as an OD tablet (with and without water; suspended in water administered via a nasogastric tube), or an IR tablet to Western healthy subjects

Parametera	Ticagrelor 90 mg				GMRs (90% CI)
	OD tablet with water (n = 30)	OD tablet without water (n = 31)	OD tablet via an NG tube (n = 33)	IR tablet (n = 33)	OD tablet with water vs. IR tablet	OD tablet without water vs. IR tablet	OD tablet via an NG tube vs. IR tablet
Ticagrelor
C max (ng/mL)	428 (25.0)	499 (34.0)	479 (32.1)	520 (29.0)	84.85 (76.77–93.78)	96.61 (88.22–105.79)	92.16 (85.59–99.25)
AUC0–∞ (ng·h/mL)	3068 (29.2)	3228 (44.2)	3226 (42.9)	3423 (41.8)	94.96 (90.27–99.89)	95.24 (89.81–100.99)	94.40 (90.26–98.73)
AUC0–t (ng·h/mL)	3023 (28.6)	3172 (42.6)	3174 (40.9)	3358 (40.0)	95.04 (90.33–99.99)	95.41 (89.94–101.21)	94.66 (90.53–98.98)
t ½ (h)b	8.02 (1.25)	8.21 (1.46)	7.99 (1.83)	8.18 (1.71)	–	–	–
t max (h)c	2.02 (1.00–4.02)	2.00 (1.00–4.00)	2.00 (0.98–4.00)	2.00 (0.98–4.00)	–	–	–
AR-C124910XX
C max (ng/mL)	118 (26.5)	126 (24.7)	126 (30.4)	129 (31.8)	89.84 (82.03–98.39)	97.45 (90.53–104.90)	97.07 (90.83–103.74)
AUC0–∞ (ng·h/mL)	1138 (19.1)	1155 (20.7)	1154 (23.6)	1197 (22.5)	94.82 (91.36–98.42)	95.71 (91.78–99.82)	96.50 (93.26–99.87)
AUC0–t (ng·h/mL)	1087 (19.7)	1104 (20.7)	1101 (20.4)	1140 (23.0)	94.67 (90.94–98.56)	96.00 (91.87–100.33)	96.56 (93.08–100.17)
t ½ (h)b	9.48 (1.43)	9.35 (1.81)	9.36 (2.18)	9.47 (2.02)	–	–	–
t max (h)c	3.00 (1.98–6.00)	3.00 (1.98–4.00)	2.00 (1.98–4.02)	2.00 (1.98–4.00)	–	–	–
Metabolite parent ratios
C max (ng/mL)	0.300 (27.5)	0.277 (40.1)	0.286 (33.3)	0.271 (32.6)	–	–	–
AUC0–∞ (ng·h/mL)	0.405 (30.0)	0.391 (42.4)	0.391 (42.2)	0.382 (43.1)	–	–	–
AUC0–t (ng·h/mL)	0.393 (29.8)	0.380 (42.7)	0.379 (43.2)	0.371 (43.4)	–	–	–

aValues are geometric mean (percentage coefficient of variation) unless otherwise indicated

bArithmetic mean (SD)

cMedian (range)

AUC area under the plasma–concentration time curve from time zero to infinity, AUC area under the plasma–concentration time curve from time zero to end of the dosing interval, CI confidence interval; C maximum plasma concentration, GMRs geometric mean ratios, IR immediate release, NG nasogastric, OD orodispersible, SD standard deviation, t half-life, t time to maximum plasma concentration

Comparison of the OD tablet (regardless of administration) with the IR tablet showed that the 90% CIs of the GMRs for ticagrelor AUC0–∞ and AUC0–t were within 80%–125%. The 90% CIs of the GMRs for ticagrelor C max were also within this acceptance range for the OD tablet taken without water, or administered via a nasogastric tube versus the IR tablet. However, ticagrelor C max for the OD tablet taken with water was ~15% (90% CI 76.77–93.78%) lower than with the IR tablet (Table 1). For AR-C124910XX, the 90% CIs of the GMRs for AUC0–∞, AUC0–t and C max were all within 80%–125% for the OD tablet (regardless of administration) versus the IR tablet (Table 1). The low-to-moderate between-subject variability was similar across treatments for ticagrelor and AR-C124910XX. The coefficient of variation of the GMR was ~25–34% for C max, and ~29%–44% for AUC for both compounds.

Plasma concentration–time curves for ticagrelor (Fig. 4a) and AR-C124910XX (Fig. 4b) following administration of an OD tablet with or without water were generally similar to those following administration of an IR tablet.

Fig. 4

Arithmetic mean (± SD) plasma concentrations of a ticagrelor b AR-C12491XX over time following administration of a 90-mg dose of ticagrelor as an OD tablet (with and without water), or an IR tablet to Japanese healthy subjects. IR immediate release, OD orodispersible, SD standard deviation

With the OD tablet with and without water and the IR tablet, ticagrelor was rapidly absorbed with a median t max of 2–3 h, and the mean t ½ was ~8 h. AR-C124910XX was rapidly formed with a median t max of ~3 h, and the mean t ½ was ~9 h (Table 2).

Table 2

Pharmacokinetic parameters and statistical analyses of ticagrelor and AR-C124910XX following administration of a 90-mg dose of ticagrelor as an OD tablet (with and without water), or an IR tablet to Japanese healthy subjects

Parametera	Ticagrelor 90 mg			GMRs (90% CI)
	OD tablet with water (n = 41)	OD tablet without water (n = 41)	IR tablet (n = 41)	OD tablet with water vs. IR tablet	OD tablet without water vs. IR tablet
Ticagrelor
C max (ng/mL)	529 (38.4)	534 (29.8)	569 (37.0)	93.16 (85.80–101.15)	93.67 (87.88–99.84)
AUC0–∞ (ng·h/mL)	3520 (45.1)	3485 (42.8)	3606 (46.3)	97.75 (94.40–101.21)	96.50 (93.31–99.80)
AUC0–t (ng·h/mL)	3462 (43.8)	3423 (41.4)	3546 (45.0)	97.76 (94.46–101.18)	96.38 (93.24–99.63)
t ½ (h)b	7.74 (1.19)	7.94 (1.19)	7.86 (1.09)	–	–
t max (h)c	3.00 (1.00–4.02)	3.00 (1.02–5.97)	2.00 (1.00–6.00)	–	–
AR-C124910XX
C max (ng/mL)	165 (31.4)	158 (36.5)	170 (35.5)	96.79 (88.27–106.14)	92.32 (85.04–100.23)
AUC0–∞ (ng·h/mL)	1547 (23.3)	1503 (24.0)	1573 (22.3)	98.46 (94.85–102.20)	95.47 (91.99–99.08)
AUC0–t (ng·h/mL)	1488 (23.5)	1441 (24.5)	1513 (22.7)	98.43 (94.75–102.25)	95.15 (91.59–98.85)
t ½ (h)b	9.13 (1.91)	9.12 (1.81)	9.05 (1.68)	–	–
t max (h)c	3.07 (2.00–6.00)	3.00 (2.00–6.02)	3.00 (1.00–8.00)	–	–
Metabolite parent ratios
C max (ng/mL)	0.340 (41.4)	0.322 (44.8)	0.327 (43.2)	–	–
AUC0–∞ (ng·h/mL)	0.480 (41.8)	0.471 (42.9)	0.476 (43.6)	–	–
AUC0–t (ng·h/mL)	0.469 (42.3)	0.460 (43.1)	0.466 (44.0)	–	–

aValues are geometric mean (percentage coefficient of variation) unless otherwise indicated

bArithmetic mean (SD)

cMedian (range)

AUC area under the plasma–concentration time curve from time zero to infinity, AUC area under the plasma–concentration time curve from time zero to end of the dosing interval, CI confidence interval; C maximum plasma concentration, GMRs geometric mean ratios, IR immediate release, OD orodispersible, SD standard deviation, t half-life, t time to maximum plasma concentration

For both ticagrelor and AR-C124910XX, the 90% CIs of the GMRs for AUC0–∞, AUC0–t and C max were all within 80–125% for the OD tablet, with and without water, versus the IR tablet (Table 2).

Safety and Tolerability

In both studies, no deaths, serious AEs or AEs leading to study discontinuation occurred. There were no clinically relevant changes in laboratory parameters, physical examinations, vital signs or ECGs during either study.

In total, 18 mild AEs, regardless of causality, were reported in 9 Western subjects. The numbers (%) of subjects with at least one AE were 3 (9.7%), 5 (15.6%), 3 (8.8%) and 2 (6.1%) with the ticagrelor OD tablet with water, without water, or via a nasogastric tube, or the IR tablet, respectively. Overall, the AEs (regardless of causality) occurring in more than one subject were dizziness (n = 2) and thrombophlebitis (n = 2). Seven mild, treatment-related AEs, identified by the investigator, were reported in five Western subjects. The numbers (%) of subjects with at least one treatment-related AE were 1 (3.2%), 3 (9.4%), 1 (2.9%) and 2 (6.1%) with the ticagrelor OD tablet with water, without water, or via a nasogastric tube, or the IR tablet, respectively. All treatment-related AEs only occurred in one subject (i.e. dizziness, headache, chest pain, fatigue, dyspnea, hematoma, and rash).

In Japanese subjects, a total of 15 AEs (all mild or moderate in severity), regardless of causality, were reported in 7 subjects. The numbers (%) of subjects with at least one AE were 3 (7.3%), 4 (9.5%), and 3 (7.3%) with the ticagrelor OD tablet with water, or without water, or the IR tablet, respectively. Overall, the AEs (regardless of causality) occurring in more than one subject were contusion (n = 3), dizziness (n = 2), headache (n = 2), and rhinorrhea (n = 2). Six treatment-related AEs, identified by the investigator, were reported in four Japanese subjects. The numbers (%) of subjects with at least one treatment-related AE were 2 (4.9%), 3 (7.1%), and 1 (2.4%) with the ticagrelor OD tablet with water, without water, or the IR tablet, respectively. The treatment-related AEs occurring in one subject only were dizziness, rhinorrhea, oropharyngeal pain, feeling hot, and pyrexia. Treatment-related headache was reported in two Japanese subjects.

Discussion

The main objective of the present studies was to compare the bioavailability of ticagrelor following administration of either an OD tablet or an IR tablet. The pharmacokinetic findings for ticagrelor and AR-C124910XX demonstrated that most comparisons were within the acceptance interval for OD versus IR tablets, except for ticagrelor C max following administration of the OD tablet with water in Western subjects. The lower boundary of the 90% CI for this parameter was outside the acceptance range of 80%–125% [38-40]. The reason for the lower C max of ticagrelor following administration of the OD tablet with water in Western subjects is unknown. In response to a European Medicines Agency (EMA) request, key pharmacokinetic data from the Western and Japanese studies were pooled. Data pooling fulfils the EMA guideline recommendation to consider all the evidence as a whole if multiple studies have been conducted with a given formulation, and some results show bioequivalence, whereas other results do not [39]. As both the Western and Japanese studies had a crossover design, and, therefore, each subject was its own internal control, pooling data from both studies is considered appropriate. Additionally, due to the crossover design, any between-subject differences in age and body weight/BMI, for example, would have no impact on C max and AUC for tablet comparisons. Based on the pooled data (Supplementary Methods), the ticagrelor OD tablet given with or without water was bioequivalent to the IR tablet as the 90% CIs of the GMRs for AUC and C max of both ticagrelor and AR-C124910XX were within the acceptance range of 80%–125% (Supplementary Table S1). Thus, overall, the results from both the present studies, and the pooled data analyses, indicate that the OD ticagrelor tablet, with or without water, could be used in place of an IR tablet.

The validity of the present studies is confirmed since the current findings are in keeping with previously reported data. The pharmacokinetics and safety following a single dose of ticagrelor have been extensively studied, including studies using the same ticagrelor IR tablet employed in the present studies [41]. In the present Western study, the ticagrelor and AR-C124910XX pharmacokinetic parameters are generally comparable to previous studies in Caucasian subjects with a single 90-mg ticagrelor dose [12, 13]. Furthermore, the pharmacokinetic parameters in the current Japanese study are also generally similar to previous studies in Asian subjects, including Chinese [18] and Japanese [19] healthy subjects and in Japanese, Asian [20], and Chinese patients with coronary artery disease [21]. With regards to safety and tolerability, a single, 90-mg dose of ticagrelor was well tolerated in both studies. Moreover, the AE profile of ticagrelor in the present studies was consistent with previous studies in Caucasian subjects [5, 12, 13, 17], and Asian subjects [18-21]. No new safety concerns with ticagrelor were identified with the OD tablet versus the IR tablet.

The present studies have some limitations. Only a single, 90-mg ticagrelor dose was evaluated, whereas, clinically, the ticagrelor dosing regimen is a 180-mg loading dose and 90 mg twice daily thereafter [7]. Furthermore, the current results in healthy subjects may not reflect those in populations of patients with ACS. In addition, the pharmacodynamic effects (i.e. platelet inhibition) were not evaluated in these studies.

The current pharmacokinetic results with the ticagrelor OD tablet, demonstrating bioequivalence with the IR tablet, are clinically important. OD tablets potentially address the medical needs of patients who are unable to take standard tablets [23, 34, 35]. Such patients include those who are unconscious, sedated, critically ill [24], elderly [25], or have dysphagia [26]. Moreover, all these scenarios are likely to be applicable to patients with cardiovascular disease [28-31] who may require antiplatelet therapy. Based on the current results, the ticagrelor OD tablet is considered a suitable alternative formulation to the 90-mg ticagrelor IR tablet for patients who are unable to swallow whole tablets, for whom there is a preference for an OD formulation, or for those who require nasogastric administration. Easy dispersal of an OD tablet in water is simpler than crushing tablets for nasogastric tube administration. Other advantages of a ticagrelor OD tablet include convenience of dosing and use in situations when no water is available [34, 35].

Alternative methods of administering ticagrelor have also been studied, i.e. crushing or chewing the standard tablets. An ex vivo study demonstrated the feasibility of administering crushed ticagrelor tablets either orally or via a nasogastric tube [42]. Subsequently, a healthy subject study showed that crushed ticagrelor tablets were bioequivalent (i.e. pharmacokinetic parameters) to whole tablets [33]. Interestingly, higher ticagrelor and AR-C124910XX plasma levels occurred in the first hour post-dosing and t max values were shorter for crushed versus whole tablets in healthy volunteers [33] and in patients with ST-elevation MI (STEMI) [43]. However, compared with the IR tablet, the ticagrelor OD tablet did not result in higher exposure to ticagrelor or AR-C124910XX at early time points post-dosing or a shorter t max in either of the present studies. Three studies evaluated the effects of chewing ticagrelor tablets, the Chewing Versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in ACS (CHEERS) study in patients with non-STEMI, the CHEERS-STEMI (similar study to CHEERS, but in patients with STEMI) and the Inhibition of Platelet Aggregation After Administration of Three Different Ticagrelor Formulations (IPAAD-Tica) study in patients with stable angina. All these studies showed that chewing two 90 mg ticagrelor tablets (180 mg loading dose) resulted in a faster onset of platelet inhibition versus a standard oral loading dose with whole tablets [44-46]. However, none of these studies reported ticagrelor or AR-C124910XX pharmacokinetic parameters. A faster onset of platelet inhibition in patients with STEMI has also been reported for crushed versus whole ticagrelor tablets [43, 47]. However, as platelet inhibition was not evaluated in the current studies, it is inappropriate to speculate on the possible pharmacodynamic effects of the ticagrelor OD tablet.

Conclusions

Following a single 90-mg dose of ticagrelor as an OD tablet to Western (with or without water, or via a nasogastric tube) or Japanese (with or without water) healthy subjects, pharmacokinetic parameters of ticagrelor and AR-C124910XX were comparable with those following administration of an IR tablet. The 90% CIs of the GMRs of C max and AUC for both compounds were within 80%–125%; except for ticagrelor C max following administration of the OD tablet with water in the Western study, which was ~15% lower than the C max with the ticagrelor IR tablet. These results indicate that ticagrelor administered as an OD tablet to Western (without water, and via a nasogastric tube) and Japanese (with/without water) subjects was bioequivalent to the IR tablet. The safety profile of OD and IR ticagrelor tablets in both studies was consistent with previous studies.

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 21 kb)

Ticagrelor, a P2Y12 receptor inhibitor, is approved as an antiplatelet agent in patients with acute coronary syndrome (90 mg twice daily with low-dose aspirin for the first year) or a history of myocardial infarction (60 mg twice daily with low-dose aspirin, 1 year after an acute coronary syndrome event).

Some patients requiring ticagrelor may have difficulty to swallow whole immediate-release (IR) tablets; thus, a ticagrelor orodispersible (OD) tablet has been developed.

Bioequivalence was demonstrated between OD tablets and IR tablets in healthy Western subjects (without water, and via a nasogastric tube) and in healthy Japanese subjects (with/without water).