Enoxaparin Sodium is Administered to Healthy Volunteers
Conditions
Brief summary
* The primary objective of the trial is to assess the single-dose relative bioavailability of Chemi Enoxaparin (80 mg/0.8 mL) and Clexane® (80 mg/0.8 mL) administered by subcutaneous (s.c.) injection, under fasting conditions in healthy volunteers. * The secondary objective of the trial is to assess safety and tolerability of Chemi Enoxaparin (80 mg/0.8 mL) and Clexane® (80 mg/0.8 mL) administered by s.c. injection, under fasting conditions in healthy volunteers.
Detailed description
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.
Interventions
DRUGEnoxaparin Sodium
comparison of bioavailability of generic Enoxaparin Sodium and Clexane
Sponsors
Chemi S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female volunteer between 18 and 55 years of age. * Subject with a BMI of 18-30 (Body Mass Index = Body weight (kg) / \[Height (m)\]2) * Subject with no clinically significant abnormal serum biochemistry, haematology, coagulation factors and urine examination values within 14 days of the first dose. * Subject with no clinically significant abnormalities in 12-lead electrocardiogram (ECG) and vital signs determined within 14 days of the first dose. * Subject with negative human immunodeficiency virus (HIV) and hepatitis B surface antigen (HbsAg) and hepatitis C virus antibody (HCV) results.
Exclusion criteria
* Subject with hypersensitivity or idiosyncratic reaction to enoxaparin and/or low molecular weight heparins, and/or pork products. * Subject with a relevant history or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease. Or with history or presence of alcoholism or drug abuse; * Subject with clinically relevant abnormal physical findings or clinically relevant abnormal laboratory values indicative of physical illness; * Female subject who is pregnant or lactating * Female subject with weight \< 45 kg or male subject with weight \< 57 kg.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC0-t (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lambda Zeta (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| t1/2 (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Tmin (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC%ex (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Cmin (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Cmax (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Cmax (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC0-t (Derived Thrombin Generation) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Cmin (Derived Thrombin Generation) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Tmin (Derived Thrombin Generation) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC0-t (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC0-inf (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Tmax (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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 |
| AUC0-inf (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Tmin (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| T1/2 (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Lambda Zeta (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC%ex (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC0-t (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| AUC0-inf (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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 |
| T1/2 (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Cmin (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Cmin is the minimun plasma activity/concentration. |
| Tmin (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Tmin is the time of Cmin. |
| AUC%ex (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Tmax (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | The ratio of anti-FXa/anti-FIIa activity was calculated for each major parameter. Tmax is the time to Cmax. |
| Lambda Zeta (Anti-FXa/Anti-FIIa Ratio) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Cmin (Tissue Factor Pathway Inhibitor, TFPI) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
| Tmax (Anti-FXa and Anti-FIIa) | At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h) | 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. |
Countries
United Kingdom
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 24 |
| 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. | 23 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 1 |
| Period 1 | Sponsor request | 1 | 0 |
Baseline characteristics
| Characteristic | Test IMP - Reference IMP | Reference IMP - Test IMP | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 23 Participants | 47 Participants |
| Region of Enrollment United Kingdom | 24 participants | 23 participants | 47 participants |
| Sex: Female, Male Female | 13 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 45 |
| other Total, other adverse events | 7 / 46 | 5 / 45 |
| serious Total, serious adverse events | 1 / 46 | 1 / 45 |
Outcome results
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-t (Anti-FXa and Anti-FIIa) | Anti-FXa | 9.6259 h*IU/mL | Standard Deviation 1.6859 |
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-t (Anti-FXa and Anti-FIIa) | Anti-FIIa | 1.0234 h*IU/mL | Standard Deviation 0.28817 |
| Clexane (Reference IMP) | AUC0-t (Anti-FXa and Anti-FIIa) | Anti-FXa | 9.3927 h*IU/mL | Standard Deviation 1.83943 |
| Clexane (Reference IMP) | AUC0-t (Anti-FXa and Anti-FIIa) | Anti-FIIa | 1.1097 h*IU/mL | Standard Deviation 0.31668 |
Comparison: Anti-FXa statistical comparison95% CI: [100.67, 105.15]
Comparison: Anti-FIIa comparison95% CI: [87.72, 97.25]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Cmax (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.8593 IU/mL | Standard Deviation 0.18056 |
| Enoxaparin Sodium Chemi (Test IMP) | Cmax (Anti-FXa and Anti-FIIa) | Anti-thrombin/factor IIa | 0.1187 IU/mL | Standard Deviation 0.03451 |
| Clexane (Reference IMP) | Cmax (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.8698 IU/mL | Standard Deviation 0.20921 |
| Clexane (Reference IMP) | Cmax (Anti-FXa and Anti-FIIa) | Anti-thrombin/factor IIa | 0.1296 IU/mL | Standard Deviation 0.03713 |
Comparison: Statistical comparison for Anti-FXa95% CI: [96.28, 102.65]
Comparison: Statistical comparison on Anti-FIIa95% CI: [86.65, 96.73]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-inf (Anti-FXa and Anti-FIIa) | Anti-FXa | 10.2789 h*IU/mL | Standard Deviation 1.71377 |
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-inf (Anti-FXa and Anti-FIIa) | Anti-FIIa | 1.1489 h*IU/mL | Standard Deviation 0.29243 |
| Clexane (Reference IMP) | AUC0-inf (Anti-FXa and Anti-FIIa) | Anti-FXa | 9.9197 h*IU/mL | Standard Deviation 1.86143 |
| Clexane (Reference IMP) | AUC0-inf (Anti-FXa and Anti-FIIa) | Anti-FIIa | 1.2926 h*IU/mL | Standard Deviation 0.40401 |
Comparison: Anti-FXA comparison95% CI: [101.68, 106.9]
Comparison: Anti-FIIa comparison95% CI: [85.38, 95.8]
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
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-inf (Anti-FXa/Anti-FIIa Ratio) | 9.1620 h*IU/mL | Standard Deviation 1.47121 |
| Clexane (Reference IMP) | AUC0-inf (Anti-FXa/Anti-FIIa Ratio) | 8.2160 h*IU/mL | Standard Deviation 1.60673 |
95% CI: [107.47, 120.53]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-inf (Tissue Factor Pathway Inhibitor, TFPI) | 140.8383 h*Unit/mL | Standard Deviation 36.06655 |
| Clexane (Reference IMP) | AUC0-inf (Tissue Factor Pathway Inhibitor, TFPI) | 173.9833 h*Unit/mL | Standard Deviation 123.89404 |
95% CI: [85.7, 105.6]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-t (Anti-FXa/Anti-FIIa Ratio) | 9.7836 h*IU/mL | Standard Deviation 1.75225 |
| Clexane (Reference IMP) | AUC0-t (Anti-FXa/Anti-FIIa Ratio) | 8.7967 h*IU/mL | Standard Deviation 1.64043 |
95% CI: [105.89, 117.17]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-t (Derived Thrombin Generation) | 3731.0710 h*nM | Standard Deviation 1375.97298 |
| Clexane (Reference IMP) | AUC0-t (Derived Thrombin Generation) | 3597.3375 h*nM | Standard Deviation 1104.52084 |
95% CI: [97.51, 108.28]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC0-t (Tissue Factor Pathway Inhibitor, TFPI) | 56.1828 h*Unit/mL | Standard Deviation 7.9106 |
| Clexane (Reference IMP) | AUC0-t (Tissue Factor Pathway Inhibitor, TFPI) | 55.7851 h*Unit/mL | Standard Deviation 8.43154 |
95% CI: [99.27, 102.47]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC%ex (Anti-FXa and Anti-FIIa) | Anti-FXa | 6.4515 percentage of total value of AUC | Standard Deviation 2.6813 |
| Enoxaparin Sodium Chemi (Test IMP) | AUC%ex (Anti-FXa and Anti-FIIa) | Anti-FIIa | 12.0593 percentage of total value of AUC | Standard Deviation 7.68842 |
| Clexane (Reference IMP) | AUC%ex (Anti-FXa and Anti-FIIa) | Anti-FXa | 4.9683 percentage of total value of AUC | Standard Deviation 1.80897 |
| Clexane (Reference IMP) | AUC%ex (Anti-FXa and Anti-FIIa) | Anti-FIIa | 12.0906 percentage of total value of AUC | Standard Deviation 9.02925 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC%ex (Anti-FXa/Anti-FIIa Ratio) | 0.8078 percentage of total AUC | Standard Deviation 0.71131 |
| Clexane (Reference IMP) | AUC%ex (Anti-FXa/Anti-FIIa Ratio) | 0.6385 percentage of total AUC | Standard Deviation 0.52118 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | AUC%ex (Tissue Factor Pathway Inhibitor, TFPI) | 58.9149 percentage of total AUC | Standard Deviation 5.07416 |
| Clexane (Reference IMP) | AUC%ex (Tissue Factor Pathway Inhibitor, TFPI) | 63.0497 percentage of total AUC | Standard Deviation 8.81 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Cmax (Anti-FXa/Anti-FIIa Ratio) | 7.4450 ratio | Standard Deviation 1.04983 |
| Clexane (Reference IMP) | Cmax (Anti-FXa/Anti-FIIa Ratio) | 6.8546 ratio | Standard Deviation 0.95651 |
95% CI: [103.93, 113.46]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Cmax (Tissue Factor Pathway Inhibitor, TFPI) | 2.4327 IU/mL | Standard Deviation 0.35998 |
| Clexane (Reference IMP) | Cmax (Tissue Factor Pathway Inhibitor, TFPI) | 2.3391 IU/mL | Standard Deviation 0.33903 |
95% CI: [101.22, 106.73]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Cmin (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.000 IU/mL | Standard Deviation 0 |
| Enoxaparin Sodium Chemi (Test IMP) | Cmin (Anti-FXa and Anti-FIIa) | Anti-FIIa | 0.002 IU/mL | Standard Deviation 0.0044 |
| Clexane (Reference IMP) | Cmin (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.000 IU/mL | Standard Deviation 0 |
| Clexane (Reference IMP) | Cmin (Anti-FXa and Anti-FIIa) | Anti-FIIa | 0.002 IU/mL | Standard Deviation 0.0042 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Cmin (Anti-FXa/Anti-FIIa Ratio) | 0.000 UI/mL | Standard Deviation 0 |
| Clexane (Reference IMP) | Cmin (Anti-FXa/Anti-FIIa Ratio) | 0.000 UI/mL | Standard Deviation 0 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Cmin (Derived Thrombin Generation) | 13.534 nM | Standard Deviation 7.63 |
| Clexane (Reference IMP) | Cmin (Derived Thrombin Generation) | 11.543 nM | Standard Deviation 6.9299 |
95% CI: [102.29, 129.08]
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Cmin (Tissue Factor Pathway Inhibitor, TFPI) | 1.261 Unit/mL | Standard Deviation 0.2277 |
| Clexane (Reference IMP) | Cmin (Tissue Factor Pathway Inhibitor, TFPI) | 1.290 Unit/mL | Standard Deviation 0.2288 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Lambda Zeta (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.0962 1/hour | Standard Deviation 0.04251 |
| Enoxaparin Sodium Chemi (Test IMP) | Lambda Zeta (Anti-FXa and Anti-FIIa) | Anti-IIa | 0.2111 1/hour | Standard Deviation 0.10435 |
| Clexane (Reference IMP) | Lambda Zeta (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.1133 1/hour | Standard Deviation 0.04337 |
| Clexane (Reference IMP) | Lambda Zeta (Anti-FXa and Anti-FIIa) | Anti-IIa | 0.1938 1/hour | Standard Deviation 0.11612 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Lambda Zeta (Anti-FXa/Anti-FIIa Ratio) | 0.6699 1/hour | Standard Deviation 0.52191 |
| Clexane (Reference IMP) | Lambda Zeta (Anti-FXa/Anti-FIIa Ratio) | 1.0937 1/hour | Standard Deviation 1.82862 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Lambda Zeta (Tissue Factor Pathway Inhibitor, TFPI) | 0.0172 1/hour | Standard Deviation 0.00323 |
| Clexane (Reference IMP) | Lambda Zeta (Tissue Factor Pathway Inhibitor, TFPI) | 0.0148 1/hour | Standard Deviation 0.0044 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | t1/2 (Anti-FXa and Anti-FIIa) | Anti-FXa | 8.4757 hours | Standard Deviation 3.22737 |
| Enoxaparin Sodium Chemi (Test IMP) | t1/2 (Anti-FXa and Anti-FIIa) | Anti-FIIa | 4.6214 hours | Standard Deviation 2.97971 |
| Clexane (Reference IMP) | t1/2 (Anti-FXa and Anti-FIIa) | Anti-FXa | 6.9507 hours | Standard Deviation 2.42567 |
| Clexane (Reference IMP) | t1/2 (Anti-FXa and Anti-FIIa) | Anti-FIIa | 6.5045 hours | Standard Deviation 8.67539 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | T1/2 (Anti-FXa/Anti-FIIa Ratio) | 2.6595 hours | Standard Deviation 2.06574 |
| Clexane (Reference IMP) | T1/2 (Anti-FXa/Anti-FIIa Ratio) | 1.9420 hours | Standard Deviation 1.47865 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | T1/2 (Tissue Factor Pathway Inhibitor, TFPI) | 41.6397 hours | Standard Deviation 8.6688 |
| Clexane (Reference IMP) | T1/2 (Tissue Factor Pathway Inhibitor, TFPI) | 57.2439 hours | Standard Deviation 46.13993 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Tmax (Anti-FXa and Anti-FIIa) | Anti-FXa | 4.0000 Hours |
| Enoxaparin Sodium Chemi (Test IMP) | Tmax (Anti-FXa and Anti-FIIa) | Anti-FIIa | 4.0000 Hours |
| Clexane (Reference IMP) | Tmax (Anti-FXa and Anti-FIIa) | Anti-FXa | 4.0000 Hours |
| Clexane (Reference IMP) | Tmax (Anti-FXa and Anti-FIIa) | Anti-FIIa | 4.0000 Hours |
Comparison: Anti-FXa comparisonp-value: 0.764295% CI: [-0.5, 0.5]Wilcoxon (Mann-Whitney)
Comparison: Anti-FIIa comparisonp-value: 0.946495% CI: [-0.5, 0.5]Wilcoxon (Mann-Whitney)
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Tmax (Anti-FXa/Anti-FIIa Ratio) | 0.9973 hours | Standard Deviation 0.28432 |
| Clexane (Reference IMP) | Tmax (Anti-FXa/Anti-FIIa Ratio) | 0.9830 hours | Standard Deviation 0.24467 |
p-value: =0.921795% CI: [-0.13, 0.13]Wilcoxon (Mann-Whitney)
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
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Tmax (Tissue Factor Pathway Inhibitor, TFPI) | 1.7500 hours | Standard Deviation 0.83178 |
| Clexane (Reference IMP) | Tmax (Tissue Factor Pathway Inhibitor, TFPI) | 1.8068 hours | Standard Deviation 1.20665 |
p-value: =0.685795% CI: [-0.25, 0.5]Wilcoxon (Mann-Whitney)
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Tmin (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.00 hours | Standard Deviation 0 |
| Enoxaparin Sodium Chemi (Test IMP) | Tmin (Anti-FXa and Anti-FIIa) | Anti-FIIa | 4.18 hours | Standard Deviation 8.538 |
| Clexane (Reference IMP) | Tmin (Anti-FXa and Anti-FIIa) | Anti-FXa | 0.00 hours | Standard Deviation 0 |
| Clexane (Reference IMP) | Tmin (Anti-FXa and Anti-FIIa) | Anti-FIIa | 6.91 hours | Standard Deviation 12.211 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Tmin (Anti-FXa/Anti-FIIa Ratio) | 0.00 hours | Standard Deviation 0 |
| Clexane (Reference IMP) | Tmin (Anti-FXa/Anti-FIIa Ratio) | 0.00 hours | Standard Deviation 0 |
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Tmin (Derived Thrombin Generation) | 3.67 hours | Standard Deviation 1.136 |
| Clexane (Reference IMP) | Tmin (Derived Thrombin Generation) | 3.64 hours | Standard Deviation 0.911 |
p-value: =0.855495% CI: [-0.5, 0.5]ANOVA
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.
Time frame: At day 1(0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16h) and Day 2 (24 and 36h)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoxaparin Sodium Chemi (Test IMP) | Tmin (Tissue Factor Pathway Inhibitor, TFPI) | 16.27 hours | Standard Deviation 5.275 |
| Clexane (Reference IMP) | Tmin (Tissue Factor Pathway Inhibitor, TFPI) | 15.55 hours | Standard Deviation 6.293 |