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PRASUGREL EFFECT ON IN VITRO BLEEDING TIME TESTS IN A SINGLE DOSE BIOEQUIVALANCE STUDY

PRASUGREL EFFECT ON IN VITRO BLEEDING TIME TESTS IN A SINGLE DOSE BIOEQUIVALANCE STUDY Ahmet İnal MD. Ph. D ERCIYES UNIVERSITY HAKAN ÇETİNSAYA GOOD CLINICAL PRACTICE AND RESEARCH CENTER/KAYSERİ/TURKEY

Indication Prasugrel hydrochloride is a thienopyridine antiplatelet drug • Prasugrel co-administered with acetylsalicylic acid

Indication Prasugrel hydrochloride is a thienopyridine antiplatelet drug • Prasugrel co-administered with acetylsalicylic acid is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (i. e. , unstable angina, non-ST segment elevation myocardial infarction or ST segment elevation myocardial infarction) undergoing primary or delayed percutaneous coronary intervention

Pharmacokinetics Prasugrel is a prodrug. It is rapidly absorbed after oral doses and undergoes

Pharmacokinetics Prasugrel is a prodrug. It is rapidly absorbed after oral doses and undergoes hydrolysis in the intestine before being metabolised by several cytochrome P 450 isoenzymes to the active metabolite • Peak plasma concentrations of the active metabolite occur in about 30 minutes. Binding of the active metabolite to human serum albumin is about 98 %. The active metabolite is further metabolised to 2 inactive compounds which are excreted in the urine and faeces; about 68 % of a dose is excreted in urine and about 27 % in faeces. The elimination half-life of the active metabolite is about 7. 4 hours

Uses and administration Prasugrel is given orally as the hydrochloride, but doses are expressed

Uses and administration Prasugrel is given orally as the hydrochloride, but doses are expressed in terms of the base; 5. 5 mg of prasugrel hydrochloride is equal to about 5 mg of base • A loading dose of 60 mg is given initially; to reduce the risk of bleeding in patients with unstable angina or non-ST segment elevation myocardial infarction who have had a coronary angioplasty within 48 hours of admission to hospital, the loading dose should not be given at the time of angioplasty, but should be given later, at the time of percutaneous coronary intervention. Prasugrel is then continued at a maintenance dose of 10 mg once daily for up to 12 months. Patients weighing under 60 kg and those aged 75 years and older should be given a maintenance dose of 5 mg once daily, although use in those aged 75 years and older is not generally recommended

Adverse events During treatment with prasugrel adverse events could appear, as generally with all

Adverse events During treatment with prasugrel adverse events could appear, as generally with all other drugs

RATIONALE OF THE STUDY AND STUDY OBJECTIVES • The objective of the study is

RATIONALE OF THE STUDY AND STUDY OBJECTIVES • The objective of the study is to compare the bioavailability and characterise the pharmacokinetic properties of the test product relative to that of the reference product containing 10 mg prasugrel after single oral dosing under fasting and fed conditions in healthy male subjects. • For this purpose the rate and extent of absorption of the first metabolite R-95913 of prasugrel compared after administration of one tablet of the test product and one tablet of the reference product under the respective condition (fasting or fed).

RATIONALE OF THE STUDY AND STUDY OBJECTIVES • Furthermore the rate and extent of

RATIONALE OF THE STUDY AND STUDY OBJECTIVES • Furthermore the rate and extent of absorption of the first metabolite R-95913 of prasugrel compared of the test product (fasting vs. fed condition) as well as of the reference product (fasting vs. fed condition). • The secondary objective of the present trial is to investigate the safety of the preparations on the basis of safety clinical and laboratory examinations (at the beginning and at the end of the trial) and registration of adverse events and/or adverse drug reactions

STUDY DESIGN AND PLAN DESCRIPTION • The study performed as a single dose, randomised,

STUDY DESIGN AND PLAN DESCRIPTION • The study performed as a single dose, randomised, open label, two-treatment, four-period and two sequence, crossover study with 20 subjects under fasting and fed conditions at one study site. • The study consisted of four treatment periods, separated by wash-out periods of at least 7 days between consecutive administrations of study medication on clinic days. • All evaluable data are supposed to be used for the safety evaluation. Follow up laboratory investigations performed within 2 - 7 days after the last blood sampling in the last treatment period. Subjects randomly assigned to treatment sequences

STUDY DESIGN AND PLAN DESCRIPTION • Healthy male subjects complying with the inclusion criteria

STUDY DESIGN AND PLAN DESCRIPTION • Healthy male subjects complying with the inclusion criteria randomly assigned to two treatment sequences. Eligibility checked in a screening examination including medical history, physical examination and a laboratory test procedure performed not more than 14 days prior to the first treatment period. • The subjects admitted for the treatment periods to the clinical trial unit latest 13 hours before drug administration

STUDY DESIGN AND PLAN DESCRIPTION • Administration under fasting conditions (treatment period I and

STUDY DESIGN AND PLAN DESCRIPTION • Administration under fasting conditions (treatment period I and treatment period II): • After overnight fasting of at least 10 hours the subjects administered 10 mg prasugrel starting at 8. 00 o'clock (time 0, administration time staggered beginning at 8: 00 o’clock for the first group of subjects). According to the randomisation code subjects received on the respective study day one tablet of the test product or one tablet of the reference product, respectively • Administration under fed conditions (treatment period III and treatment period IV): • After overnight fasting of at least 10 hours and after taking a standardised high fat, high-calorie breakfast 30 minutes before drug administration the subjects administered 10 mg prasugrel at 8: 00 o'clock (time 0, administration time staggered beginning at 8: 00 o’clock for the first group of subjects).

STUDY DESIGN AND PLAN DESCRIPTION • According to the randomisation code subjects received on

STUDY DESIGN AND PLAN DESCRIPTION • According to the randomisation code subjects received on the respective study day one tablet of the test product or one tablet of the reference product, respectively. • A total of 22 blood samples collected before and up to 24 hours after each drug administration. The subjects discharged after the 24 hours blood sample is taken. • A follow up examination consisting of a physical examination, vital signs and laboratory tests performed within 2 - 7 days after the last blood sampling in the last treatment period. • A total of 20 subjects included in the study

SELECTION OF STUDY POPULATION • A total of 20 subjects, who fulfill the inclusion

SELECTION OF STUDY POPULATION • A total of 20 subjects, who fulfill the inclusion criteria, do not meet any of the exclusion criteria, who have given written informed consent, entered into the study. • Drug assays and statistical analysis of the data performed on all plasma samples of those subjects who complete the study according to the Clinical Study Protocol or who partially complete the study with evaluable data. • Subjects recruited from the volunteer pool of the Erciyes University Hakan Cetinsaya GCP and Research Center

INCLUSION CRITERIA • · Healthy, Caucasian, male subjects 18 – 55 years of age

INCLUSION CRITERIA • · Healthy, Caucasian, male subjects 18 – 55 years of age • · Body mass index within the range of 18. 5 – 30 kg/m 2 • · Findings within the range of clinical acceptability in medical history and physical examination unless the clinical investigator considers the deviation to be irrelevant for the purpose of the study • · Laboratory values within the normal range unless the clinical investigator considers the deviation to be irrelevant for the purpose of the study

INCLUSION CRITERIA • · Normal ECG and vital signs (normal blood pressure and heart

INCLUSION CRITERIA • · Normal ECG and vital signs (normal blood pressure and heart rate measured under stabilised conditions at screening visit after at least 5 minutes of rest in sitting position: systolic blood pressure 100 - 140 mm. Hg, diastolic blood pressure 60 - 90 mm. Hg and heart rate 50 - 100 beats per minute; normal body temperature (35. 4 °C – 37. 8 °C)), or abnormalities which the clinical investigator does not consider a disqualification for participation in the study • · Willingness to undergo a pre-study physical examination and pre- and post-study laboratory investigations • · Ability to comprehend subject information and informed consent given in written form • · Non-smokers and no usage of any other tobacco products

EXCLUSION CRITERIA • · History of hypersensitivity to the study drug or any related

EXCLUSION CRITERIA • · History of hypersensitivity to the study drug or any related drugs or to any of the excipients • · History or presence of any clinically significant cardiovascular, pulmonary, hepatobiliary, renal, haematological, gastrointestinal, endocrinologic, immunologic, dermatologic, neurological, psychiatric, metabolic, musculoskeletal, or malignant disease • · Clinically significant abnormal laboratory values, ECG findings or vital signs during screening; • Clinically significant illness or surgery within 4 weeks prior to dosing

EXCLUSION CRITERIA • · History of, or current compulsive alcohol abuse (more than a

EXCLUSION CRITERIA • · History of, or current compulsive alcohol abuse (more than a total of 10 drinks (e. g. beer, wine, spirits) weekly); or regular exposure to other substances of abuse • · Regular consumption of beverages or food containing methylxanthines (e. g. coffee, tea, cola, caffeine containing sodas, chocolate) equivalent to more than 500 mg methylxanthines per day • · History of drug abuse or use of soft drugs, e. g. marihuana within 6 months of screening or hard drugs, e. g. cocaine, amphetamines, phencyclidine within 12 months of screening

EXCLUSION CRITERIA Positive urine screen for drugs of abuse · Smokers or usage of

EXCLUSION CRITERIA Positive urine screen for drugs of abuse · Smokers or usage of any other tobacco products · Positive cotinine test · Positive alcohol test · Donation or loss of blood equal to or exceeding 500 ml during 90 days before the first administration of study medication • · Positive testing for HIV, HBs. Ag and HCV • · Participation in another clinical study at same time or within the preceding 3 months (calculated from the date of the final examination of the previous study) except for previous bioequivalence trials in which case at least 8 weeks are sufficient or after at least ten elimination half lives of the previous experimental drug, whichever is longer • · Any use of drug, prescribed or OTC (inclusive herbal remedies), within 2 weeks (or within six elimination half lives of this medication, whichever is longer) prior to the first administration of study medication • • •

EXCLUSION CRITERIA • Intake of enzyme-inducing or organotoxic within 4 weeks before start of

EXCLUSION CRITERIA • Intake of enzyme-inducing or organotoxic within 4 weeks before start of the clinical trial • · Medication with products known to alter the major organs or systems such as CYP 3 A 4 inducers (e. g. dexamethasone, phenytoin, oxcarbazepine, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's Wort), CYP 1 A 2 inhibitors (e. g. fluvoxamine, ciprofloxacin), CYP 3 A 4 inhibitors (e. g. ketoconazole, itraconazole, erythromycin, clarithromycin), CYP 2 C 9 inhibitors (such as voriconazole) any other CYP 3 A 4 metabolized drugs (e. g. triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-Co. A reductase inhibitors, i. e. statins), CYP 2 D 6 metabolized drugs (e. g. warfarin, metoprolol), and histamine antagonist (e. g. loratadine, fexofenadine, ebastine, prometazine, quetiapine, cimetidine, ranitidine) within 2 months prior to IMP administration

EXCLUSION CRITERIA • · Special diet due to any reason, e. g. vegetarians •

EXCLUSION CRITERIA • · Special diet due to any reason, e. g. vegetarians • · Unwillingness or inability to comply with the study protocol or study-related procedures (e. g. difficulty to stay fasting, consume the standardised meals, or swallow tablets; difficult venous access).

METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS • The study carried out according to

METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS • The study carried out according to a two-treatment, fourperiod and two-sequence crossover design at one study site. • After the screening period the subjects who are selected for enrolment assigned to subject enrolment numbers (numbers 001 -020) corresponding to the order of their entry into the study. • The subjects randomly allocated to different treatment sequences. In the first treatment period the subjects received either one tablet of the test product or one tablet of the reference product under fasting conditions. In the second treatment period the subjects crossover to received the respective other product under fasting conditions. In the third treatment period the subjects received either one tablet of the test product or one tablet of the reference product under fed conditions. In the fourth treatment period the subjects crossover to received the respective other product under fed conditions

INSTRUCTION FOR SUBJECTS • Before the screening examination subjects instructed to: • · take

INSTRUCTION FOR SUBJECTS • Before the screening examination subjects instructed to: • · take no other drug (OTC or prescription medications inclusive herbal remedies) 2 weeks prior to and during the present study • · stay fasting for at least 10 hours (water is allowed up to 1 hour prior to the examination). • Before and up to 24 hours after dosing subjects will be instructed to: • · abstain from alcohol for 7 days before each drug administration and until last blood sampling in each period • · abstain from caffeine or quinine containing drinks (e. g. bitter lemon, tonic water) for 24 hours before each drug administration and until last blood sampling in each period • · abstain from grapefruit products (fresh, canned, or frozen) or grapefruit-juices for 7 days before each drug administration and until last blood sampling in each period

INSTRUCTION FOR SUBJECTS • · abstain from vigorous physical exercises (i. e. running, swimming,

INSTRUCTION FOR SUBJECTS • · abstain from vigorous physical exercises (i. e. running, swimming, biking, dancing, gardening) during the study • · visit the clinical trial unit at least 13 hours before each drug administration and to stay hospitalised up to 24 hours after each drug administration • · stay fasting for at least 10 hours before and 4 hours after each drug administration • · do not chew, break or touch the study drug (if a subject chews or breaks the study drug, that subject removed from the study)

INSTRUCTION FOR SUBJECTS Administration under fasting conditions · take the respective study medication in

INSTRUCTION FOR SUBJECTS Administration under fasting conditions · take the respective study medication in sitting position together with 240 ml non-carbonated potable water • Administration under fed conditions • · take a standardised high fat, high calorie breakfast 30 min before drug administration (the composition of the meal corresponds approximately to 150 kcal from protein, 250 kcal from carbohydrate and 500 – 600 kcal from fat with a total caloric content of approximately 800 – 1000 kcal) according to the Guideline on the Investigation of Bioequivalence and according to the FDA recommendation which consists of: • 2 eggs fried in butter • 2 strips of sausages • 2 slices of toast with butter • 110 grams of hash brown potatoes • 240 millilitre of whole milk • · consume the entire standardised high fat, high calorie breakfast within 30 minutes

INSTRUCTION FOR SUBJECTS • · remain in sitting position for 4 hours after drug

INSTRUCTION FOR SUBJECTS • · remain in sitting position for 4 hours after drug administration without doing strenuous physical activity (standing and walking only allowed if procedurally required) • · take standard hospital meals 4 and 10 hours after each drug administration • · drink water ad libitum until 1 hour before each drug administration • · drink water ad libitum after 1 hour after each drug administration. • Before the post-study examination subjects will be instructed to: • · stay fasting for at least 10 hours (water is allowed up to 1 hour prior to the examination

TESTING PROCEDURE During two weeks before the start of the study a prestudy examination

TESTING PROCEDURE During two weeks before the start of the study a prestudy examination performed including the following parameters Personal data · Medical history · Physical examination (including: height, weight) · 12 -lead ECG · Vital signs (including: blood pressure, heart rate, temperature) • • Urine drug screen: Benzodiazepine Cocaine Amphetamines Opiates Barbiturates Cannabis

TESTING PROCEDURE

TESTING PROCEDURE

FINAL MEDICAL EXAMINATION AT THE END OF THE STUDY • Within 2 - 7

FINAL MEDICAL EXAMINATION AT THE END OF THE STUDY • Within 2 - 7 days after last blood sampling in the last treatment period, the subjects undergoes a follow up examination which includes the following parameters: • · Questioning for subjective well-being • · Physical examination (including: weight) • · 12 -lead ECG • · Vital signs (including: blood pressure, heart rate, temperature) • · Laboratory test (after at least 10 hours fasting) • · Questioning for adverse events • The results recorded in the Case Report Forms. • The laboratory test consist of the parameters listed in first examination with exception of HIV, Hepatitis B and HCV serology

IN VITRO BLEEDING TIME TEST Collagen ADP and Epinephrine were performed during first and

IN VITRO BLEEDING TIME TEST Collagen ADP and Epinephrine were performed during first and final laboratory examinations. PFA 100 P 2 Y kit was used for the measurement of this test • • • • • • Col adp time/sec Before After 61. 0 87. 0 89. 0 90. 0 82. 0 80. 0 86. 0 82. 0 88. 0 82. 0 68. 0 97. 0 79. 0 67. 0 74. 0 75. 0 70. 0 75. 0 78. 0 82. 0 69. 0 68. 0 76. 0 81. 0 62. 0 74. 0 95. 0 89. 0 94. 0 105. 0 71. 0 67. 0 76. 0 68. 0 69. 0 61. 0 70. 0 68. 0 Col epi time/sec Before After 93. 0 88. 0 117. 0 108. 0 127. 0 95. 0 91. 0 102. 0 124. 0 114. 0 109. 0 87. 0 144. 0 115. 0 118. 0 93. 0 104. 0 100. 0 95. 0 90. 0 112. 0 107. 0 103. 0 122. 0 125. 0 88. 0 86. 0 156. 0 102. 0 128. 0 131. 0 106. 0 94. 0 115. 0 72. 0 102. 0 63. 0 111. 0 93. 0

Statistical analyses • Paired sample test was used to analyze the data • No

Statistical analyses • Paired sample test was used to analyze the data • No significant difference between collagen adp groups • After collagen epinephrine time decreased from first collagen epinephrine time • Both in vitro bleeding time test was not prolonged

RESULT • When used in the treatment of prasugrel it was expected to extend

RESULT • When used in the treatment of prasugrel it was expected to extend in vitro bleeding time test. But, in our study, in vitro bleeding time or remained unchanged or decreased in the first and final laboratory examinations

RECOMMENDATION • there is no need for bleeding time tests in a single dose

RECOMMENDATION • there is no need for bleeding time tests in a single dose bioequivalence study

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 LET US MEET AGAIN. . We welcome you to our future conferences of

LET US MEET AGAIN. . We welcome you to our future conferences of Conference Series LLC through 8 th World Congress on Bioavailability & Bioequivalence: BA/BE Studies Summit June 26 -29, 2017 at San Diego, USA http: //bioavailability-bioequivalence. pharmaceuticalconferences. com/