Therapeutic Equivalency
Conditions
Keywords
Bioequivalence
Brief summary
The drug investigated in this study is Rivaroxaban, a novel, once-daily, oral anticoagulant for the prevention (prophylaxis) of deep vein thrombosis (DVT) which may lead to a pulmonary embolism (PE) in people undergoing knee or hip replacement surgery. The purpose of this study is to establish bioequivalence of 2 immediate-release tablet treatments with Rivaroxaban: 2\*5 mg tablets and 1\*10 mg tablet will be given to healthy volunteers under fasting conditions; they will be administered as single oral doses in 2 periods. Both periods will be separated by a 7-day washout phase. Thus, the bioequivalence represents the primary study objective. As a secondary objective, this treatment will be assessed in terms of safety and tolerability. Bioequivalence will be evaluated and verified on the basis of pharmacokinetic data. Blood samples of the volunteers will be taken at specific points in time; these samples will be analyzed using various statistical methods to establish pharmacokinetic characteristics required to compare the 2 treatments. The planned treatments with Rivaroxaban will be considered bioequivalent if specific criteria defined in the study protocol are met. The study will be conducted in one center in Germany. 28 subjects meeting the inclusion criteria will participate. They will be treated according to a single-dose, randomized, 2-way cross-over, non-placebo-controlled design.
Interventions
DRUGRivaroxaban (Xarelto, BAY59-7939)
Single oral dose of rivaroxaban administered under fasting conditions 2\*5 mg tablet in first intervention period and 1\*10 mg tablet in second intervention period (after washout period)
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects * 18 to 45 years of age * Body mass index (BMI) between 18 and 30 kg/m2
Exclusion criteria
* Conspicuous findings (medical history, screening) * History of relevant diseases (internal organs, central nervous system or other organs) * Medical disorder, condition or history of such that would impair the subject's ability to participate or complete this study in the opinion of the investigator or the sponsor * Febrile illness within 1 week before the start of the study * History of severe allergies, non-allergic drug reactions, or multiple drug allergies * Hypersensitivity to the investigational drug, the control agent and/or to inactive constituents * Known coagulation disorders, known disorders with increased bleeding risk, known sensitivity to common causes of bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity After Single Dose (AUC) Incl. Bioequivalence (BE) Evaluation | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample (AUC is defined as area under the concentration vs. time curve from zero to infinity after single (first) dose). |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to Last Quantifiable Concentration [AUC (0-tn)] Incl. Bioequivalence (BE) Evaluation | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; \[AUC (0-tn)\] is defined as AUC from time 0 to the last data point above the Lower Limit of Quantification. |
| Maximum Observed Drug Concentration in Plasma After Single Dose Administration (Cmax) Incl. Bioequivalence (BE) Evaluation | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Drug Concentration in Plasma After Single Dose (Tmax) | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Area Under the Plasma Concentration Versus Time Curve Divided by Dose Per kg Body Weight (AUCnorm) | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; AUCnorm is defined as AUC divided by dose per kg body weight. |
| Half-life Associated With the Terminal Slope (t½) | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. |
| Maximum Observed Drug Concentration in Plasma After Single Dose Administration Divided by Dose Per kg Body Weight (Cmax, Norm) | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight. |
| Mean Residence Time (MRT) | 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration | The mean residence time is the average time that the molecules introduced into the body stay in the body. |
Countries
Germany
Participant flow
Recruitment details
All participants (part.) recruited by CRS Clinical-Research-Services Moenchengladbach GmbH, Hindenburgstrasse 304 - 306, 41061 Moenchengladbach, Germany. 28 part. were planned to be enrolled.
Pre-assignment details
37 participants screened; 9 participants were screening failures; 28 participants were included in the study. Safety analysis: 27 individuals were analyzed in the group with 2\*5mg, 27 individuals were analyzed in the group with 1\*10mg.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) First 2*5 mg , Then 1*10 mg Single oral dose of rivaroxaban administered under fasting conditions 2\*5 mg tablet in first intervention period and 1\*10 mg tablet in second intervention period (after washout period) | 14 |
| Rivaroxaban (Xarelto, BAY59-7939) First 1*10 mg, Then 2*5 mg Single oral dose of rivaroxaban administered under fasting conditions 1\*10 mg tablet in first intervention period and 2\*5 mg tablet in second intervention period (after washout period) | 14 |
| Total | 28 |
Baseline characteristics
| Characteristic | Rivaroxaban (Xarelto, BAY59-7939) First 2*5 mg , Then 1*10 mg | Rivaroxaban (Xarelto, BAY59-7939) First 1*10 mg, Then 2*5 mg | Total |
|---|---|---|---|
| Age, Continuous | 31.6 Years STANDARD_DEVIATION 5.8 | 31.3 Years STANDARD_DEVIATION 10.5 | 31.4 Years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 27 | 6 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity After Single Dose (AUC) Incl. Bioequivalence (BE) Evaluation
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample (AUC is defined as area under the concentration vs. time curve from zero to infinity after single (first) dose).
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity After Single Dose (AUC) Incl. Bioequivalence (BE) Evaluation | 1374 µg*hr/L | Geometric Coefficient of Variation 29.3 |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity After Single Dose (AUC) Incl. Bioequivalence (BE) Evaluation | 1268 µg*hr/L | Geometric Coefficient of Variation 30.7 |
p-value: 0.043890% CI: [101.59, 115.57]ANOVA
Primary
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Last Quantifiable Concentration [AUC (0-tn)] Incl. Bioequivalence (BE) Evaluation
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; \[AUC (0-tn)\] is defined as AUC from time 0 to the last data point above the Lower Limit of Quantification.
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Last Quantifiable Concentration [AUC (0-tn)] Incl. Bioequivalence (BE) Evaluation | 1354 µg*hr/L | Geometric Coefficient of Variation 29.8 |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Last Quantifiable Concentration [AUC (0-tn)] Incl. Bioequivalence (BE) Evaluation | 1252 µg*hr/L | Geometric Coefficient of Variation 31.6 |
p-value: 0.051490% CI: [101.31, 115.54]ANOVA
Primary
Maximum Observed Drug Concentration in Plasma After Single Dose Administration (Cmax) Incl. Bioequivalence (BE) Evaluation
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Maximum Observed Drug Concentration in Plasma After Single Dose Administration (Cmax) Incl. Bioequivalence (BE) Evaluation | 179.8 µg/L | Geometric Coefficient of Variation 31.1 |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Maximum Observed Drug Concentration in Plasma After Single Dose Administration (Cmax) Incl. Bioequivalence (BE) Evaluation | 161.1 µg/L | Geometric Coefficient of Variation 38.7 |
p-value: 0.068590% CI: [101.14, 123.23]ANOVA
Secondary
Area Under the Plasma Concentration Versus Time Curve Divided by Dose Per kg Body Weight (AUCnorm)
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; AUCnorm is defined as AUC divided by dose per kg body weight.
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Area Under the Plasma Concentration Versus Time Curve Divided by Dose Per kg Body Weight (AUCnorm) | 10.79 kg*hr/L | Geometric Coefficient of Variation 33 |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Area Under the Plasma Concentration Versus Time Curve Divided by Dose Per kg Body Weight (AUCnorm) | 9.957 kg*hr/L | Geometric Coefficient of Variation 36.4 |
Secondary
Half-life Associated With the Terminal Slope (t½)
Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Half-life Associated With the Terminal Slope (t½) | 8.932 hr | Geometric Coefficient of Variation 48.6 |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Half-life Associated With the Terminal Slope (t½) | 8.721 hr | Geometric Coefficient of Variation 55.7 |
Secondary
Maximum Observed Drug Concentration in Plasma After Single Dose Administration Divided by Dose Per kg Body Weight (Cmax, Norm)
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight.
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Maximum Observed Drug Concentration in Plasma After Single Dose Administration Divided by Dose Per kg Body Weight (Cmax, Norm) | 1.412 kg/L | Geometric Coefficient of Variation 35.3 |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Maximum Observed Drug Concentration in Plasma After Single Dose Administration Divided by Dose Per kg Body Weight (Cmax, Norm) | 1.265 kg/L | Geometric Coefficient of Variation 46 |
Secondary
Mean Residence Time (MRT)
The mean residence time is the average time that the molecules introduced into the body stay in the body.
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Mean Residence Time (MRT) | 8.874 hr | Geometric Coefficient of Variation 22 |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Mean Residence Time (MRT) | 9.284 hr | Geometric Coefficient of Variation 28.2 |
Secondary
Time to Reach Maximum Drug Concentration in Plasma After Single Dose (Tmax)
Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: 0 min, 15 min, 30 min, 45 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 24 hours, 36 hours, 48 hours and 72 hours post administration
Population: N=26 valid for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) 2*5 mg | Time to Reach Maximum Drug Concentration in Plasma After Single Dose (Tmax) | 2.50 hr |
| Rivaroxaban (Xarelto, BAY59-7939) 1*10 mg | Time to Reach Maximum Drug Concentration in Plasma After Single Dose (Tmax) | 2.50 hr |