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This is an open-label, randomised, single-dose, 2-way crossover study to determine the comparative bioavailability of enoxaparin sodium from the Chemi Enoxaparin s.c. (80 mg/0.8mL) with that from the reference IMP, Clexane® s.c. (80 mg/0.8mL), following single dose administration in healthy male and female subjects.
Each subject received each treatment over two separate treatment periods under fasting conditions. Each dosing day for male subjects will be separated by a washout period of at least 7 days. The study comprised a pre-study screen (within 14 days of the first dose), followed by 2 Treatment Periods (1 and 2). During each treatment period, subjects will reside at Simbec from the evening before dosing (Day 1), until at least 36 h post dose (evening of Day 2). On admission (Day -1), subjects will provide a urine sample for a drugs of abuse screen; this sample will also be tested to confirm a negative pregnancy result in female volunteers.
A single dose of the randomised treatment will be given on the morning of Day 1 following an overnight fast and blood PK/PD samples collected from pre-dose up to 36 h post dose (14 samples). Safety will also be evaluated at specified times throughout the study.
The post study visit will be conducted on Day 2 (36 h post-dose) of Treatment Period 2.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Enoxaparin Sodium Chemi | Experimental | Enoxaparin Sodium Chemi and Clexane will be administered to healthy subjects. Each subject will receive each treatment over two separate treatment periods under fasting conditions. |
|
| Clexane | Experimental | Enoxaparin Sodium Chemi and Clexane will be administered to healthy subjects. Each subject will receive each treatment over two separate treatment periods under fasting conditions. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Enoxaparin Sodium | Drug | comparison of bioavailability of generic Enoxaparin Sodium and Clexane |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cmax (Anti-FXa and Anti-FIIa) | Cmax is the maximum measured plasma activity/concentration. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC0-t (Anti-FXa and Anti-FIIa) | AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII). thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Measure | Description | Time Frame |
|---|---|---|
| AUC0-inf (Anti-FXa and Anti-FIIa) | AUC0-inf is the area under the activity/concentration-time curve from time 0 extrapolated to infinity. It was calculated as the sum of AUC0-t plus the ratio of the last measurable value to the elimination rate constant. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Paolo Bettica, MD | Italfarmaco S.p.A. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Simbec Research Ltd | Merthyr Tydfil | CF48 4DR | United Kingdom |
The study comprised a screening visit and 2 treatment periods. Only two doses were scheduled to be administered: first dose (period 1) - wash out (at least 7 days) - 2nd dose (period 2) - wash out period (at least 7 days). Each treatment period was of 2 days duration. Screening assessments: from Day -14 to Day -1.
Forty-seven (47) subjects (23 male and 24 female) were enrolled in the study. The subjects were selected from a large panel who offered their services as healthy volunteers for the purpose of undertaking REC and Regulatory Authority-approved studies on drug safety, absorption and disposition.
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| ID | Title | Description |
|---|---|---|
| FG000 | Test IMP - Reference IMP | These patients reveiced the following sequence: Test IMP: A single-dose of 80mg/0.8 mL Chemi Enoxaparin. Reference IMP: A single-dose of 80mg/0.8 mL Clexane® Each dose was administered s.c. into the left or right side of the abdomen (alternating sides with treatment period). Each dose contained 80 mg enoxaparin sodium (equivalent to 8,000 international units (IU) anti-factor Xa (anti-FXa activity) in 0.8 mL water for injection. Subjects remained in an upright position whilst receiving each dose and for 4 h afterwards. There were at least 7 days between each dose administration for males and female subjects of nonchildbearing potential. Female subjects of child bearing potential underwent a washout period of approximately 28 days. |
| FG001 | Reference IMP - Test IMP | These patients reveiced the following sequence: Reference IMP: A single-dose of 80mg/0.8 mL Clexane® Test IMP: A single-dose of 80mg/0.8 mL Chemi Enoxaparin. Each dose was administered s.c. into the left or right side of the abdomen (alternating sides with treatment period). Each dose contained 80 mg enoxaparin sodium (equivalent to 8,000 international units (IU) anti-factor Xa (anti-FXa activity) in 0.8 mL water for injection. Subjects remained in an upright position whilst receiving each dose and for 4 h afterwards. There were at least 7 days between each dose administration for males and female subjects of nonchildbearing potential. Female subjects of child bearing potential underwent a washout period of approximately 28 days. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
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| Washout |
| ||||||||||||||||||||||
| Period 2 |
| ||||||||||||||||||||||
| Washout |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Test IMP - Reference IMP | These patients reveiced the following sequence: Test IMP: A single-dose of 80mg/0.8 mL Chemi Enoxaparin. Reference IMP: A single-dose of 80mg/0.8 mL Clexane® Each dose was administered s.c. into the left or right side of the abdomen (alternating sides with treatment period). Each dose contained 80 mg enoxaparin sodium (equivalent to 8,000 international units (IU) anti-factor Xa (anti-FXa activity) in 0.8 mL water for injection. Subjects remained in an upright position whilst receiving each dose and for 4 h afterwards. There were at least 7 days between each dose administration for males and female subjects of nonchildbearing potential. Female subjects of child bearing potential underwent a washout period of approximately 28 days. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cmax (Anti-FXa and Anti-FIIa) | Cmax is the maximum measured plasma activity/concentration. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | IU/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
Throughout the study: day 1 (pre-dose,0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h), Day 2 (24 and 36h), and post-study follow-up. Follow-up assessments were classified as 'End of study assessments'. They were performed on Day 2, 36 h post-dose, prior to discharging the subject.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Enoxaparin Sodium Chemi | Enoxaparin Sodium Chemi and Clexane will be administered to healthy subjects. Each subject will receive each treatment over two separate treatment periods under fasting conditions. Enoxaparin Sodium: comparison of bioavailability of generic Enoxaparin Sodium and Clexane |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fibrous dysplasia | Congenital, familial and genetic disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Paolo Bettica, MD | Chemi SpA (Part of Italfarmaco Group) | +39 02 64431 | p.bettica@italfarmaco.com |
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| ID | Term |
|---|---|
| C000711671 | enoxaparin sodium |
| D017984 | Enoxaparin |
| ID | Term |
|---|---|
| D006495 | Heparin, Low-Molecular-Weight |
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
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| Enoxaparin Sodium | Drug | comparison of bioavailability of generic Enoxaparin Sodium and Clexane |
|
|
| At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Tmax (Anti-FXa and Anti-FIIa) | Tmax is the time to Cmax. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti-FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Lambda Zeta (Anti-FXa and Anti-FIIa) | Lambda zeta is the apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma activity/concentration vs time curve. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| t1/2 (Anti-FXa and Anti-FIIa) | T1/2 is the apparent first-order terminal elimination half-life calculated as 0.693/kel.Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Tmin (Anti-FXa and Anti-FIIa) | Tmin is the time of Cmin. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC%ex (Anti-FXa and Anti-FIIa) | AUC%ex is the residual area, i.e. the percentage of the area under the curve (AUC) extrapolated to infinity observed from Tlast to infinity. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti-FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Cmin (Anti-FXa and Anti-FIIa) | Cmin is the minimum plasma activity/concentration. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Cmax (Tissue Factor Pathway Inhibitor, TFPI) | Cmax is the maximum measured plasma activity/concentration. Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Cmax (Anti-FXa/Anti-FIIa Ratio) | Cmax is the maximum measured plasma activity/concentration. The ratio of anti-FXa/anti-FIIa activity was calculated for each parameter. Reults are presented as derived ratio of PK parameters. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC0-t (Derived Thrombin Generation) | AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Cmin (Derived Thrombin Generation) | Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. Cmin is the minimum plasma activity/concentration. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Tmin (Derived Thrombin Generation) | Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. Tmin is the time of Cmin. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC0-t (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC0-inf (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. AUC0-inf is the area under the activity/concentration-time curve from time 0 extrapolated to infinity. It was calculated as the sum of AUC0-t plus the ratio of the last measurable value to the elimination rate constant. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Tmax (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Tmax is the time to Cmax | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Cmin (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Cmin is the minimum plasma activity/concentration. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Tmin (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Tmin is the time of Cmin. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| T1/2 (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. T1/2 is the apparent first-order terminal elimination half-life calculated as 0.693/kel. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Lambda Zeta (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI)[5], which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Lambda zeta is the apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma activity/concentration vs time curve. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC%ex (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also release tissue factor pathway inhibitor (TFPI)[5], which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. AUC%ex is the residual area, i.e. the percentage of the area under the curve (AUC) extrapolated to infinity observed from Tlast to infinity. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC0-t (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC0-inf (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. AUC0-inf is the area under the activity/concentration-time curve from time 0 extrapolated to infinity. It was calculated as the sum of AUC0-t plus the ratio of the last measurable value to the elimination rate constant | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| T1/2 (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. T1/2 is the apparent first-order terminal elimination half-life calculated as 0.693/kel. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Cmin (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Cmin is the minimun plasma activity/concentration. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Tmin (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Tmin is the time of Cmin. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| AUC%ex (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. AUC%ex is the residual area, i.e. the percentage of the area under the curve (AUC) extrapolated to infinity observed from Tlast to infinity. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Tmax (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Tmax is the time to Cmax. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| Lambda Zeta (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Lambda zeta is the apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma activity/concentration vs time curve. | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | Reference IMP - Test IMP | These patients reveiced the following sequence: Reference IMP: A single-dose of 80mg/0.8 mL Clexane® Test IMP: A single-dose of 80mg/0.8 mL Chemi Enoxaparin. Each dose was administered s.c. into the left or right side of the abdomen (alternating sides with treatment period). Each dose contained 80 mg enoxaparin sodium (equivalent to 8,000 international units (IU) anti-factor Xa (anti-FXa activity) in 0.8 mL water for injection. Subjects remained in an upright position whilst receiving each dose and for 4 h afterwards. There were at least 7 days between each dose administration for males and female subjects of nonchildbearing potential. Female subjects of child bearing potential underwent a washout period of approximately 28 days. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Enoxaparin Sodium Chemi (Test IMP) | Enoxaparin Sodium Chemi (i.e. Test IMP) was administered to healthy subjects. A single dose contained 80 mg enoxaparin sodium (equivalent to 8,000 international units (IU) anti-factor Xa (anti-FXa activity) in 0.8 mL water for injection. It was administered s.c . into the right or left side of the abdomen (alternating sides with treatment period). |
| OG001 | Clexane (Reference IMP) | Clexane (i.e. Reference IMP) was administered to healthy subjects. A single dose contained 80 mg enoxaparin sodium (equivalent to 8,000 international units (IU) anti-factor Xa (anti-FXa activity) in 0.8 mL water for injection. It was administered s.c . into the right or left side of the abdomen (alternating sides with treatment period). |
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| Primary | AUC0-t (Anti-FXa and Anti-FIIa) | AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII). thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | h*IU/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC0-inf (Anti-FXa and Anti-FIIa) | AUC0-inf is the area under the activity/concentration-time curve from time 0 extrapolated to infinity. It was calculated as the sum of AUC0-t plus the ratio of the last measurable value to the elimination rate constant. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | h*IU/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Tmax (Anti-FXa and Anti-FIIa) | Tmax is the time to Cmax. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti-FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Median | Full Range | Hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Lambda Zeta (Anti-FXa and Anti-FIIa) | Lambda zeta is the apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma activity/concentration vs time curve. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | 1/hour | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | t1/2 (Anti-FXa and Anti-FIIa) | T1/2 is the apparent first-order terminal elimination half-life calculated as 0.693/kel.Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Tmin (Anti-FXa and Anti-FIIa) | Tmin is the time of Cmin. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC%ex (Anti-FXa and Anti-FIIa) | AUC%ex is the residual area, i.e. the percentage of the area under the curve (AUC) extrapolated to infinity observed from Tlast to infinity. Blood samples (2 x 10 mL) for determination of plasma anti-FIIa and anti-FXa were collected from a forearm vein into a Citrate Sarstedt Monovette at the following time-points (at day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)) and kept frozen until analysis. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti-FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | percentage of total value of AUC | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Cmin (Anti-FXa and Anti-FIIa) | Cmin is the minimum plasma activity/concentration. Enoxaparin exerts its anti-coagulant effect primarily via interaction with anti-thrombin III (ATIII), thereby enhancing the inhibitory effect of ATIII on activated factor Xa (FXa) and thrombin/factor IIa (FIIa). As enoxaparin cannot be measured directly in blood, the PK of enoxaparin have been studied on the basis of its effect on clotting mechanisms, particularly the inhibition of FXa (anti-FXa) and FIIa (anti- FIIa) activity. Results are presented as derived plasma PK parameters. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | IU/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Cmax (Tissue Factor Pathway Inhibitor, TFPI) | Cmax is the maximum measured plasma activity/concentration. Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. | PK population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | IU/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Cmax (Anti-FXa/Anti-FIIa Ratio) | Cmax is the maximum measured plasma activity/concentration. The ratio of anti-FXa/anti-FIIa activity was calculated for each parameter. Reults are presented as derived ratio of PK parameters. | Posted | Mean | Standard Deviation | ratio | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC0-t (Derived Thrombin Generation) | AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | h*nM | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Cmin (Derived Thrombin Generation) | Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. Cmin is the minimum plasma activity/concentration. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | nM | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Tmin (Derived Thrombin Generation) | Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. Tmin is the time of Cmin. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC0-t (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | h*Unit/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC0-inf (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. AUC0-inf is the area under the activity/concentration-time curve from time 0 extrapolated to infinity. It was calculated as the sum of AUC0-t plus the ratio of the last measurable value to the elimination rate constant. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | h*Unit/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Tmax (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Tmax is the time to Cmax | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Cmin (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Cmin is the minimum plasma activity/concentration. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | Unit/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Tmin (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Tmin is the time of Cmin. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | T1/2 (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI), which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. T1/2 is the apparent first-order terminal elimination half-life calculated as 0.693/kel. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Lambda Zeta (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also releases tissue factor pathway inhibitor (TFPI)[5], which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. Lambda zeta is the apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma activity/concentration vs time curve. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | 1/hour | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC%ex (Tissue Factor Pathway Inhibitor, TFPI) | Enoxaparin also release tissue factor pathway inhibitor (TFPI)[5], which is thought to contribute to anti-coagulant activity, by inhibiting FXa generation and free FXa. AUC%ex is the residual area, i.e. the percentage of the area under the curve (AUC) extrapolated to infinity observed from Tlast to infinity. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | percentage of total AUC | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC0-t (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. AUC0-t is the area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | h*IU/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC0-inf (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. AUC0-inf is the area under the activity/concentration-time curve from time 0 extrapolated to infinity. It was calculated as the sum of AUC0-t plus the ratio of the last measurable value to the elimination rate constant | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | h*IU/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | T1/2 (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. T1/2 is the apparent first-order terminal elimination half-life calculated as 0.693/kel. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Cmin (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Cmin is the minimun plasma activity/concentration. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | UI/mL | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Tmin (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Tmin is the time of Cmin. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | AUC%ex (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. AUC%ex is the residual area, i.e. the percentage of the area under the curve (AUC) extrapolated to infinity observed from Tlast to infinity. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | percentage of total AUC | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Tmax (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Tmax is the time to Cmax. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | hours | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| Secondary | Lambda Zeta (Anti-FXa/Anti-FIIa Ratio) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Lambda zeta is the apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma activity/concentration vs time curve. | PK Population: All subjects who received study medication in both treatment periods, had sufficient plasma activity/concentration-time profiles and who did not violate the protocol in such a way that may have invalidated or biased the results (major protocol violators) were included in the PK analysis. | Posted | Mean | Standard Deviation | 1/hour | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) |
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| 0 |
| 46 |
| 1 |
| 46 |
| 7 |
| 46 |
| EG001 | Clexane | Enoxaparin Sodium Chemi and Clexane will be administered to healthy subjects. Each subject will receive each treatment over two separate treatment periods under fasting conditions. Enoxaparin Sodium: comparison of bioavailability of generic Enoxaparin Sodium and Clexane | 0 | 45 | 1 | 45 | 5 | 45 |
| Cellulitis | Infections and infestations | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Syncope | Nervous system disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Eczema | Skin and subcutaneous tissue disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Ligament sprain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 / 17.1 | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 17.0 / 17.1 | Systematic Assessment |
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Not provided
Not provided
| D002241 |
| Carbohydrates |
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Anti-FIIa comparison |
| least square mean difference ratio |
| 92.37 |
| 2-Sided |
| 95 |
| 87.72 |
| 97.25 |
Geometric least square means are being compared. |
| Equivalence |
Following logarithmic transformation, AUC0-t values were subjected to an analysis of variance (ANOVA), including fixed effects for sequence, period, treatment and subject nested within sequence. |
| Anti-FIIa |
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Anti-FIIa comparison |
| least square mean ratio |
| 90.44 |
| 2-Sided |
| 95 |
| 85.38 |
| 95.8 |
Geometric least square means are being compared. |
| Equivalence |
Following logarithmic transformation, AUC0-inf values were subjected to an analysis of variance (ANOVA), including fixed effects for sequence, period, treatment and subject nested within sequence |
| Anti-FIIa comparison | Wilcoxon (Mann-Whitney) | 0.9464 | least square mean ratio | 0 | 2-Sided | 95 | -0.5 | 0.5 | Geometric least square means are being compared. | Equivalence | An assessment of tmax was performed using the Wilcoxon matched pairs test. In addition, a 95 % non-parametric CI was constructed for the median difference in tmax based on the method of Campbell and Gardner. |
| Anti-IIa |
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| Anti-FIIa |
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| Anti-FIIa |
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