Study to Assess the Bioavailability of Ticagrelor OD Tablet vs. IR Tablet

Study to evaluate the bioavailability of ticagrelor OD tablets administered with water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets.

• Ticagrelor OD tablet (90 mg single dose) administered with 200 ml of water (Drug), also known as Treatment A: 90 mg single dose
• Ticagrelor OD tablet (90 mg single dose) administered without water (Drug), also known as Treatment B: 90 mg single dose
• Ticagrelor OD tablet (90 mg single dose) suspended in water administered via nasogastric tube (Drug), also known as Treatment C: 90 mg single dose
• Brilique®, Ticagrelor IR tablet (90 mg) administered with 200mL of water (Drug), also known as Treatment D: 90 mg single dose

Primary outcomes

• Maximum Observed Plasma Concentration (Cmax) of Ticagrelor and Its Active Metabolite AR-C124910XX. [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period).
• Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Analyte Concentration (AUC[0-t]) of Ticagrelor and Its Active Metabolite AR-C124910XX. [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period).
• Area Under Plasma Concentration-time Curve From Zero to Infinity (AUC [0-∞]). [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period).

Secondary outcomes

• Time to Reach Maximum Observed Concentration (Tmax) of Ticagrelor and Its Active Metabolite AR-C124910XX. [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period).
• Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) of Ticagrelor and Its Active Metabolite AR-C124910XX. [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period).
• Ratio of Metabolite Cmax to Parent Cmax, Adjusted for Differences in Molecular Weights (MRCmax) of Metabolite AR-C124910XX. [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Assesssment of MRCmax (ratio of metabolite Cmax to parent Cmax, adjusted for differences in molecular weights) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet when administered with water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets.
• Ratio of Metabolite AUC(0-t) to Parent AUC(0-t), Adjusted for Differences in Molecular Weights (MRAUC[0-t]) of Metabolite AR-C124910XX. [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Assesssment of MRAUC(0-t) (Ratio of metabolite AUC(0-t) to parent AUC(0-t), adjusted for differences in molecular weights) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet when administered with water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets.
• Ratio of Metabolite AUC [0-∞] to Parent AUC [0-∞], Adjusted for Differences in Molecular Weights (MRAUC [0-∞]) of Metabolite AR-C124910XX. [0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period.]: Assesssment of MRAUC \[0-∞\] (Ratio of metabolite AUC \[0-∞\] to parent AUC \[0-∞\], adjusted for differences in molecular weights) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet when administered with water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets.
• Percentage of Participants With Adverse Events (AEs). [SAEs were recorded from the signing of informed consent and AEs were recorded from randomisation until the final follow-up visit.]: An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. The term AE is used generally to include any AE whether serious or non-serious. A serious AE (SAE) is an AE that fulfills one or more of the following criteria: results in death, is immediately life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; is a congenital abnormality or birth defect; is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above.
• Mean Change From Baseline for Vital Signs of Supine Blood Pressure (SBP) and Diastolic BP (DBP). [Day 1 (2, 4 hours post-dose) and Day 2 (24 hours post-dose).]: The following variables were collected after the participants had rested in the supine position for at least 5 minutes: SBP and DBP.
• Mean Change From Baseline for Vital Signs in Supine Pulse Rate. [Day 1 (2, 4 hours post-dose) and Day 2 (24 hours post-dose).]: Vital signs were collected after the participant has rested in the supine position for at least 5 minutes.
• Participants With Significant Findings in 12-Lead Electrocardiography (ECG). [At screening and at follow-up.]: A 12-lead ECG was obtained after the participant rested in supine position for at least 10 minutes. The study physician was to judge the overall interpretation as normal or abnormal. If abnormal, it was decided as to whether or not the abnormality was clinically significant and the reason for the abnormality was recorded.
• Participants With Clinically Significant Findings in Hematology, Clinical Chemistry and Urinalysis. [At screening, at admission on Day -1 to each treatment period and at follow-up.]: Participants were assessed through each laboratory variables for any significant abnormalities. Hematology assessments included white blood cell count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and others. Clinical chemistry assessment included testing levels of sodium, potassium, urea, creatinine, albumin, calcium, glucose (fasting) and others. Urinalysis assessment included glucose, protein, blood and microscopy (if positive for blood or protein).

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture. - Females must have a negative pregnancy test at screening and on each admission to the clinical unit, must not be lactating, and must be of non-childbearing potential, confirmed at screening by fulfilling one of the following criteria: Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the postmenopausal range or Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. - Have a body mass index (BMI) between 18.5 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive. -Able to understand, read and speak the German language.

Exclusion Criteria: - History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the potential subject at risk because of participation in the study, or influence the results or the potential subject's ability to participate in the study.

* Any abnormalities in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), urea, creatinine, thyroid-stimulating hormone (TSH), International Normalised Ratio (INR), activated partial thromboplastin time (aPTT), white blood cell (WBC) count, haemoglobin (Hb) or platelet count. Any other abnormal haematology, clinical chemistry, coagulation or urinalysis results, as judged with an unacceptable deviation that is considered to be clinically significant by the investigator.
* Any clinically significant abnormal findings in vital signs, as judged by the investigator. at screening and at baseline (Day -1 of Treatment period 1), defined as:

  * Systolic blood pressure < 90mmHg or ≥ 140 mmHg
  * Diastolic blood pressure < 50mmHg or ≥ 90 mmHg
  * Pulse < 50 or > 85 beats per minute (bpm)
* Current smokers or those who have smoked or used nicotine products within the previous 3 months.
* History of haemophilia, von Willebrand's disease, lupus anticoagulant, or other diseases/syndromes that can either alter or increase the propensity for bleeding.
* A personal history of vascular abnormalities including aneurysms; a personal history of severe haemorrhage, hematemesis, melena, haemoptysis, severe epistaxis, severe thrombocytopenia, intracranial haemorrhage; or rectal bleeding within 1 year prior to screening; or history suggestive of peptic ulcer disease; or at the discretion of the investigator.
* History of a clinically significant non-traumatic bleed or clinically significant bleeding risk, as judged by the investigator.
* Use of aspirin, ibuprofen, non-steroidal anti-inflammatory drugs (NSAIDs), or any other drug known to increase the propensity for bleeding for 2 weeks before randomisation.
* Platelet count less than 150 x 109/L.

Criteria applicable to insertion of a nasogastric tube:

* History of severe midface trauma and/or recent nasal surgery.
* History of coagulation abnormality, oesophageal varices or stricture, recent banding or cautery of oesophageal varices, and/or alkaline ingestion, at the discretion of the investigator.

Participant flow

Outcome results

• Maximum Observed Plasma Concentration (Cmax) of Ticagrelor and Its Active Metabolite AR-C124910XX. (Primary), Geometric mean, ng/mL: Treatment A 428 +/- 25.0; Treatment B 499 +/- 34.0; Treatment C 479 +/- 32.1; Treatment D 520 +/- 29.0
• Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Analyte Concentration (AUC[0-t]) of Ticagrelor and Its Active Metabolite AR-C124910XX. (Primary), Geometric mean, h·ng/mL: Treatment A 3023 +/- 28.6; Treatment B 3172 +/- 42.6; Treatment C 3174 +/- 40.9; Treatment D 3358 +/- 40.0
• Area Under Plasma Concentration-time Curve From Zero to Infinity (AUC [0-∞]). (Primary), Geometric mean, h·ng/mL: Treatment A 3068 +/- 29.2; Treatment B 3228 +/- 44.2; Treatment C 3226 +/- 42.9; Treatment D 3423 +/- 41.8
• Time to Reach Maximum Observed Concentration (Tmax) of Ticagrelor and Its Active Metabolite AR-C124910XX. (Secondary), Median, h: Treatment A 2.02 (1.00 to 4.02); Treatment B 2.00 (1.00 to 4.00); Treatment C 2.00 (0.98 to 4.00); Treatment D 2.00 (0.98 to 4.00)
• Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) of Ticagrelor and Its Active Metabolite AR-C124910XX. (Secondary), Mean, h: Treatment A 8.02 (1.00 to 4.02); Treatment B 8.21 (1.00 to 4.00); Treatment C 7.99 (0.98 to 4.00); Treatment D 8.18 (0.98 to 4.00)
• Ratio of Metabolite Cmax to Parent Cmax, Adjusted for Differences in Molecular Weights (MRCmax) of Metabolite AR-C124910XX. (Secondary), Geometric mean, ratio: Treatment A 0.300 (1.98 to 6.00); Treatment B 0.277 (1.98 to 4.00); Treatment C 0.286 (1.98 to 4.02); Treatment D 0.271 (1.98 to 4.00)
• Ratio of Metabolite AUC(0-t) to Parent AUC(0-t), Adjusted for Differences in Molecular Weights (MRAUC[0-t]) of Metabolite AR-C124910XX. (Secondary), Geometric mean, ratio: Treatment A 0.393 (1.98 to 6.00); Treatment B 0.380 (1.98 to 4.00); Treatment C 0.379 (1.98 to 4.02); Treatment D 0.371 (1.98 to 4.00)
• Ratio of Metabolite AUC [0-∞] to Parent AUC [0-∞], Adjusted for Differences in Molecular Weights (MRAUC [0-∞]) of Metabolite AR-C124910XX. (Secondary), Geometric mean, ratio: Treatment A 0.405 (1.98 to 6.00); Treatment B 0.391 (1.98 to 4.00); Treatment C 0.391 (1.98 to 4.02); Treatment D 0.382 (1.98 to 4.00)
• Percentage of Participants With Adverse Events (AEs). (Secondary), Number, percentage of participants: Treatment A 9.7; Treatment B 15.6; Treatment C 8.8; Treatment D 6.1
• Mean Change From Baseline for Vital Signs of Supine Blood Pressure (SBP) and Diastolic BP (DBP). (Secondary), Mean, mmHg: Treatment A -2 +/- 8; Treatment B -2 +/- 7; Treatment C -1 +/- 8; Treatment D 3 +/- 8
• Mean Change From Baseline for Vital Signs in Supine Pulse Rate. (Secondary), Mean, bpm: Treatment A 0 +/- 5; Treatment B -1 +/- 5; Treatment C -1 +/- 6; Treatment D 0 +/- 5
• Participants With Significant Findings in 12-Lead Electrocardiography (ECG). (Secondary), Number, participants: Treatment A 0 +/- 6; Treatment B 0 +/- 7; Treatment C 0 +/- 7; Treatment D 0 +/- 7
• Participants With Clinically Significant Findings in Hematology, Clinical Chemistry and Urinalysis. (Secondary), Number, participants: Treatment A 0; Treatment B 0; Treatment C 0; Treatment D 0

Adverse events

Time frame: Serious adverse events were recorded from the signing of the informed consent and adverse events were recorded from randomization until the final follow-up visit.

Other adverse events by term

• Rainard Fuhr, Dr. med., Principal investigator, PAREXEL International GmbH, Berlin