Bioequivalence, AUC, Cmax, Pharmacokinetics
Conditions
Keywords
Clopidogrel, Zyllt, Plavix, Phase I, Healthy Subjects, Pharmacokinetics, Bioequivalence
Brief summary
This study will be an open-label, randomised, three-way crossover study in healthy male and female subjects, performed at a single centre. The objective of the study is to assess the bioequivalence between one test formulation (Clopidogrel 75 mg tablet (commercial blister from KRKA) and two reference formulations (Clopidogrel 75 mg tablet \[Plavix, sourced in US and Japan\]).
Detailed description
Study to evaluate the bioequivalence of orally administered European source clopidogrel tablets and US and Japanese source clopidogrel tablets.
Interventions
DRUGClopidogrel
European clopidogrel tablets, 75 mg (test) versus Japanese clopidogrel tablets, 75 mg (reference); European clopidogrel tablets, 75 mg (test) versus US clopidogrel tablets, 75 mg (reference)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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 • if of non child-bearing potential, confirmed at screening by fulfilling one of the following criteria: * Post-menopausal 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 post-menopausal range. * Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. • if of child-bearing potential and are sexually active must use, with their partner, 2 approved methods of highly effective contraception from the time of IMP administration until 3 months after the last dose of IMP. * Have a body mass index between 18,5 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive. * Be 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. * 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, haematemesis, 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. * Use of aspirin, ibuprofen, NSAIDS, or any other drug known to increase the propensity for bleeding for 2 weeks before randomisation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero Extrapolated to Infinity (AUC(0-inf)) | 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose | Comparison of the pharmacokinetic profile in terms of plasma concentration-time curve from time zero extrapolated to infinity, AUC(0-inf), of clopidogrel sourced in Europe and Japan. |
| Pharmacokinetics of Clopidogrel by Assessment of Observed Maximum Plasma Concentration (Cmax) | 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose | Comparison of the pharmacokinetic profile in terms of observed maximum plasma concentration, taken directly from the individual concentration-time curve, Cmax, of clopidogrel sourced in Europe and the US. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC(0-last)) | 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose | Comparison of the pharmacokinetic profile in terms of the area under the plasma concentration-curve from time zero to the time of last quantifiable clopidogrel or SR26334 concentration, AUC(0-last), of clopidogrel sourced in Europe and the US. |
Countries
Germany
Participant flow
Recruitment details
Participants recruited at PAREXEL Early Phase Clinical Unit Berlin, Germany between August 2014 and September 2014.
Pre-assignment details
84 participants recruited; 144 screened, 60 excluded (59 did not meet inclusion criteria and 1 refused participation)
Participants by arm
| Arm | Count |
|---|---|
| First European, Then Japanese, Then US Clopidogrel A single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA
\- test) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 3 | 14 |
| First European, Then US, Then Japanese Clopidogrel A single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi-Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 3 | 14 |
| First Japanese, Then European, Then US Clopidogrel A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi-Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 3 | 14 |
| First Japanese, Then US, Then European Clopidogrel A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi-Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 3 | 14 |
| First US, Then European, Then Japanese Clopidogrel A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 1, a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 3 | 14 |
| First US, Then Japanese, Then European Clopidogrel A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 3 | 14 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Period | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
| First Washout Period | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 |
| First Washout Period | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | First European, Then US, Then Japanese Clopidogrel | First Japanese, Then European, Then US Clopidogrel | First Japanese, Then US, Then European Clopidogrel | First European, Then Japanese, Then US Clopidogrel | First US, Then European, Then Japanese Clopidogrel | First US, Then Japanese, Then European Clopidogrel | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 11 | 36 years STANDARD_DEVIATION 10 | 35 years STANDARD_DEVIATION 8 | 33 years STANDARD_DEVIATION 9 | 34 years STANDARD_DEVIATION 9 | 36 years STANDARD_DEVIATION 11 | 35 years STANDARD_DEVIATION 9 |
| BMI (Body Mass Index) | 24.7 kg/m^2 STANDARD_DEVIATION 3.5 | 23.4 kg/m^2 STANDARD_DEVIATION 2.9 | 24.1 kg/m^2 STANDARD_DEVIATION 2.7 | 23.7 kg/m^2 STANDARD_DEVIATION 3.1 | 23.0 kg/m^2 STANDARD_DEVIATION 3.1 | 23.9 kg/m^2 STANDARD_DEVIATION 3.1 | 23.8 kg/m^2 STANDARD_DEVIATION 3 |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 14 participants | 14 participants | 14 participants | 14 participants | 12 participants | 13 participants | 81 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 0 participants | 0 participants | 2 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized White | 14 participants | 13 participants | 14 participants | 13 participants | 12 participants | 13 participants | 79 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 7 Participants | 7 Participants | 4 Participants | 4 Participants | 37 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 7 Participants | 7 Participants | 10 Participants | 10 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 81 | 18 / 80 | 22 / 82 | 38 / 83 |
| serious Total, serious adverse events | 0 / 81 | 0 / 80 | 0 / 82 | 0 / 83 |
Outcome results
Primary
Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero Extrapolated to Infinity (AUC(0-inf))
Comparison of the pharmacokinetic profile in terms of plasma concentration-time curve from time zero extrapolated to infinity, AUC(0-inf), of clopidogrel sourced in Europe and Japan.
Time frame: 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose
Population: The pharmacokinetic population consisted of 79 subjects, i.e. all subjects in the safety population for whom AUC(0-last) and Cmax could be calculated for clopidogrel for the test treatment (European) and at least one of the reference treatments (Japanese, US). AUC(0-inf) could not be reliably calculated for many of these subjects.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| European Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero Extrapolated to Infinity (AUC(0-inf)) | 1.05 ng*h/mL | Geometric Coefficient of Variation 139 |
| Japanese Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero Extrapolated to Infinity (AUC(0-inf)) | 0.992 ng*h/mL | Geometric Coefficient of Variation 117.9 |
| US Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero Extrapolated to Infinity (AUC(0-inf)) | 1.09 ng*h/mL | Geometric Coefficient of Variation 106.9 |
90% CI: [92.27, 118.19]
Comparison: The analysis was conducted using an analysis of variance (ANOVA) including fixed effects for treatment, sequence, period and subject within sequence. All pharmacokinetic parameters were log-transformed prior to analysis. Bioequivalence was concluded, when the 90% confidence interval (CI) for the geometric LS mean ratios were fully contained within the predefined equivalence limits of 0.80 to 1.2590% CI: [81.12, 116.45]
Primary
Pharmacokinetics of Clopidogrel by Assessment of Observed Maximum Plasma Concentration (Cmax)
Comparison of the pharmacokinetic profile in terms of observed maximum plasma concentration, taken directly from the individual concentration-time curve, Cmax, of clopidogrel sourced in Europe and the US.
Time frame: 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose
Population: The pharmacokinetic population consisted of 79 subjects, i.e. all subjects in the safety population for whom AUC(0-last) and Cmax could be calculated for clopidogrel for the test treatment (European) and at least one of the reference treatments (Japanese, US)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| European Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Observed Maximum Plasma Concentration (Cmax) | 0.551 ng/mL | Geometric Coefficient of Variation 122.6 |
| Japanese Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Observed Maximum Plasma Concentration (Cmax) | 0.511 ng/mL | Geometric Coefficient of Variation 150.6 |
| US Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Observed Maximum Plasma Concentration (Cmax) | 0.521 ng/mL | Geometric Coefficient of Variation 122.4 |
90% CI: [95.46, 122.33]
90% CI: [95.22, 117.53]
Secondary
Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC(0-last))
Comparison of the pharmacokinetic profile in terms of the area under the plasma concentration-curve from time zero to the time of last quantifiable clopidogrel or SR26334 concentration, AUC(0-last), of clopidogrel sourced in Europe and the US.
Time frame: 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose
Population: The pharmacokinetic population consisted of 79 subjects, i.e. all subjects in the safety population for whom AUC(0-last) and Cmax could be calculated for clopidogrel for the test treatment (European) and at least one of the reference treatments (Japanese, US)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| European Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC(0-last)) | 0.705 h*ng/mL | Geometric Coefficient of Variation 114.8 |
| Japanese Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC(0-last)) | 0.751 h*ng/mL | Geometric Coefficient of Variation 116.5 |
| US Clopidogrel Tablets, 75 mg | Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC(0-last)) | 0.767 h*ng/mL | Geometric Coefficient of Variation 107.1 |
90% CI: [87.12, 101.29]
90% CI: [84.91, 99.75]