To evaluate the relative bioavailability of ticagrelor for the different formulations. A randomized cross-over design has been chosen to minimize the effects of between-subject variability and any period effects on the overall results.
This study will be an open-label, randomized, 4-period, 4-treatment, cross-over, single-center, single-dose study to assess the relative bioavailability of different formulations of ticagrelor in approximately 44 healthy adult subjects. Eligible subjects will be healthy male and female aged 18 to 55 years, with a body weight of 55 to 100 kg and a body mass index (BMI) of 18 to 30 kg/m2. Of the 44 randomized subjects, at least 36 evaluable subjects should be at the end of the last treatment period. Subjects will be randomized to 1 of 4 treatment sequences and will receive single oral doses of 4 different formulations of ticagrelor under fasted conditions. Subjects will fast for at least 10 hours prior to administration of Investigational Medicinal Products (IMPs). No fluids will be allowed apart from water which can be given until 1 hour prior to administration of the IMP and then from 2 hours after administration of the IMP. A meal can be given 4 hours after administration of the IMP.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
44
A P2Y12 receptor inhibitor provided as granule for suspension.
A P2Y12 receptor inhibitor provided as pediatric tablets to be swallowed whole.
A P2Y12 receptor inhibitor provided as pediatric tablets suspended in water.
Research Site
Berlin, Germany
Maximum observed plasma concentration (Cmax)
* To determine the relative bioavailability of ticagrelor granule for oral suspension and the pediatric ticagrelor tablet to the commercial ticagrelor tablet in healthy subjects. * To determine the relative bioavailability of ticagrelor pediatric tablet taken whole and the pediatric tablet dispersed in water to the granule for oral suspension in healthy subjects. * To evaluate the bioequivalence between the pediatric ticagrelor tablet taken whole and the pediatric ticagrelor tablet dispersed in water in healthy subjects.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Area under plasma concentration-time curve from zero to infinity (AUC)
* To determine the relative bioavailability of ticagrelor granule for oral suspension and the pediatric ticagrelor tablet to the commercial ticagrelor tablet in healthy subjects. * To determine the relative bioavailability of ticagrelor pediatric tablet taken whole and the pediatric tablet dispersed in water to the granule for oral suspension in healthy subjects. * To evaluate the bioequivalence between the pediatric ticagrelor tablet taken whole and the pediatric ticagrelor tablet dispersed in water in healthy subjects.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose.
Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(0-t))
To compare the pharmacokinetic (PK) profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Time to reach maximum observed plasma concentration, taken directly from the individual concentration-time curve (tmax).
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A P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (unstable angina, non-ST (S and T waves) elevation MI or ST elevation MI) and in patients with a history of MI
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz).
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Terminal rate constant, estimated by log-linear regression of the terminal part of the concentration-time curve (λz).
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Apparent clearance, estimated as dose divided by AUC (ticagrelor only) (CL/F).
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Apparent volume of distribution at the terminal phase, estimated by dividing the apparent clearance (CL/F) by λz (ticagrelor only) (Vz/F).
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Ratio of metabolite Cmax to parent Cmax, adjusted for differences in molecular weights (MRCmax).
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Ratio of metabolite AUC(0-t) to parent AUC(0-t), adjusted for differences in molecular weights (MRAUC(0-t)).
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Ratio of metabolite AUC to parent AUC, adjusted for differences in molecular weights (MRAUC)
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
Time frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Number of patients with Adverse Events (AEs)
To assess the adverse events as a criteria of safety and tolerability variables.
Time frame: From screening (day -28) until follow-up/early termination (ET) (Day 5 to Day 10 (after treatment Period 4/ET))
Vital sign (systolic and diastolic blood pressure [BP])
To assess the vital signs as a criteria of safety and tolerability variables.
Time frame: At screening (Day -28), admission (Day -1), treatment periods 1, 2, 3, 4 (Day 1 - 3) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Vital sign (pulse rate)
To assess the vital signs as a criteria of safety and tolerability variables.
Time frame: At screening (Day -28), admission (Day -1), treatment periods 1, 2, 3, 4 (Day 1 - 3) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Twelve-lead electrocardiograms (ECGs)
To assess the cardiovascular system functioning as a criteria of safety and tolerability variables.
Time frame: At screening (Day -28) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Physical examination
To assess the physical examination as a criteria of safety and tolerability variables.
Time frame: At screening (Day -28) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Laboratory assessments (hematology and clinical chemistry)
To assess the hematology and clinical chemistry as a criteria of safety and tolerability variables.
Time frame: At screening (Day -28), admission (day -1) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Laboratory assessments (Urinalysis (dipstick))
To assess the urinalysis as a criteria of safety and tolerability variables.
Time frame: At screening (Day -28), admission (day -1) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))