Transcript ahmet-inal-erciyes-university-turkey-61260428

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PRASUGREL EFFECT ON IN VITRO
BLEEDING TIME TESTS IN A SINGLE
DOSE BIOEQUIVALANCE STUDY
Ahmet İnal MD.PhD
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 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
hydrolysis in the intestine
before being metabolised
by several cytochrome
P450 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 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
other drugs
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 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, 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 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
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 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
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
• · Body mass index within the range of 18.5 – 30
kg/m2
• · 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 rate measured under stabilised conditions at
screening visit after at least 5 minutes of rest in sitting
position: systolic blood pressure 100 - 140 mmHg, diastolic
blood pressure 60 - 90 mmHg 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
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 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
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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, HBsAg 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 the clinical trial
• · Medication with products known to alter the major
organs or systems such as CYP3A4 inducers (e.g.
dexamethasone, phenytoin, oxcarbazepine,
carbamazepine, rifampicin, phenobarbital or Hypericum
perforatum, also known as St. John's Wort), CYP1A2
inhibitors (e.g. fluvoxamine, ciprofloxacin), CYP3A4
inhibitors (e.g. ketoconazole, itraconazole, erythromycin,
clarithromycin), CYP2C9 inhibitors (such as voriconazole)
any other CYP3A4 metabolized drugs (e.g.
triazolobenzodiazepines, dihydropyridine calcium channel
blockers, certain HMG-CoA reductase inhibitors, i.e.
statins), CYP2D6 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
• · 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 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 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, 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 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
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
pre-study 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)
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Urine drug screen:
Benzodiazepine
Cocaine
Amphetamines
Opiates
Barbiturates
Cannabis
TESTING PROCEDURE
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 final
laboratory examinations. PFA
100 P2Y kit was used for the
measurement of this test
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Col adp time/sec
Before After
61.0 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
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
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 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 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 bioequivalence study
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