Pharmacokinetics, Safety Issues
Conditions
Keywords
Bevacizumab, Biosimilar, Antineoplastic Agents, Bioequivalence, Immunogenicity, safety, healthy male volunteers
Brief summary
The aim of the Clinical study is to evaluate the pharmacokinetic and safety profile of a new formulation of Bevacizumab (Zutrab®, Argentinian origin) when compared to two already marketed formulations of Bevacizumab Avastin® (reference product) and Cizumab® (Indian origin), to establish similarity.
Detailed description
Three-way bridge phase 1 trial. It is conducted in healthy, male adult subjects, it is single-dose, double-blind, parallel groups, randomized and balanced. Blood samples are collected for up to 90 days, to determine serum drug concentration and anti-drug antibodies. Safety and tolerability are also assessed.
Interventions
BIOLOGICALBevacizumab
Single-dose infusion
Sponsors
FP Clinical Pharma S.R.L.
Syngene
Laboratorios Richmond S.A.C.I.F.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Study subjects must be willing and able to provide written informed consent * Subjects of study, volunteers, adults, healthy. * Study subjects whose safety and complementary laboratory tests are within normal values or which, in the Investigator's opinion, do not have clinical relevance: blood count, erythrosedimentation, hepatogram, urea, creatinine, glucose, coagulogram, serology for HIV, hepatitis B , hepatitis C, complete urinalysis, detection of drugs of abuse in urine and electrocardiogram. * Sample taken for immunogenicity * Body mass index between 19 and 27 kg / m2 at the screening visit. * Subjects of study preferably non-smokers. * Men with a partner of childbearing age must agree that their partner uses an adequate contraceptive method before entering the study and for at least 3 months after the end of the study. It is understood as a contraceptive method suitable to any hormonal contraceptive method or intrauterine device (which should be established before the start of the study) and the use of a spermicide as a barrier method. The use of a barrier method alone or sexual abstinence is not considered adequate. * Subjects must agree not to donate sperm during the study and for 4 months after treatment.
Exclusion criteria
* History of pulmonary, gastrointestinal, hepatic, renal, hematological, endocrine-metabolic, neurological or psychiatric illnesses (depressive disorders, in particular) at the time of taking the anamnesis and the physical examination during the first visit of the Protocol of Clinical research. * History of gastrointestinal surgeries (except uncomplicated appendectomy, at least 3 months old). * History of major surgery, surgical biopsy and / or history of significant trauma within 1 month of the screening visit. * Specifically, pre-existing gastrointestinal conditions such as abdominal fistulas, gastrointestinal perforation within 6 months of the screening visit. * Specifically, preexisting gastrointestinal conditions such as acute or subacute intestinal occlusion. * Specifically, history of inflammatory bowel disease. * History of hemorrhagic diseases and / or coagulopathies and / or thromboembolic events. * History of heart and vascular diseases: specifically myocardial infarction, unstable angina, cerebrovascular accident, uncontrolled arterial hypertension and cardiac arrhythmias. * Background or current history of alcohol or drug abuse. * Blood donation within 3 months prior to selection. * Administration of any other drug under investigation or participation in a clinical research trial within 3 months prior to the planned participation in this Clinical Research Protocol. * History of clinically significant diseases or disorders that, in the opinion of the Investigator, may impede the participation of the study subject for safety reasons or that may influence the results of the same as well as the ability of the study subject to participate in the Clinical Research Protocol. * History of hypersensitivity to bevacizumab and / or any of the excipients. * Study subjects who present contraindications to therapy * Study subjects who have received (2 weeks before) or are receiving aspirin or clopidogrel * The study subjects must have suspended any pharmacological treatments at least 2 weeks before the initiation of this Clinical Research Protocol. * Non-cooperative study subjects * Study subjects employed by the Researcher or the Clinical-Pharmacokinetic Research Unit, with direct participation in the Clinical Research Protocol or other clinical protocols under the Direction of the Researcher or the Clinical-Pharmacokinetic Research Unit * Physical findings and laboratory analyses: * Cardiac, pulmonary, gastrointestinal, hepatic, renal, hematological, endocrine-metabolic, neurological disease or psychiatric disorder (depressive disorders, in particular) * Evidence of ulcers, unhealed wounds or bone fractures. * Clinically significant abnormalities in any laboratory analysis, and electrocardiogram * Positive serology for HIV, hepatitis B, hepatitis C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Serum Concentration of Bevacizumab (Cmax) | 0, 0.33, 0.5, 1, 1.5 hours during infusion, 0.33, 0.66, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512 hours post-infusion | Cmax will be obtained directly from the serum concentration-time curve |
| Area Under the Serum Concentration-time Curve of Bevacizumab (ABC0-t) | Day 1 to Day 63 | Area under the serum concentration-time curve from time zero to the last experimental point, will be calculated by the trapezoidal rule |
| Area Under the Serum Concentration- Time Curve ob Bevacizumab (ABC0-∞) | Day 1 to Day 63 | Area under the serum concentration- time curve from time zero to infinity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systemic Clearance (CL) | Day 1 to Day 63 | To assess pharmacokinetic parameters |
| Time to Reach the Peak Serum Concentration (Tmax) | Day 1 to Day 63 | Time to reach the peak serum concentration, which will be obtained directly from the serum concentration curve- time |
| Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | Screening and end of study (Day 63) | To assess the immunogenic potential of the products under investigation, samples were taken for the determination of anti-bevacizumab serum antibodies for each randomized volunteer subject. |
| Distribution Volume | Day 1 to Day 63 | To assess pharmacokinetic parameters |
| Terminal Elimination Rate Constant (λz) | Day 1 to Day 63 | Terminal elimination rate constant will be calculated by linear regression analysis of the semi-logarithmic curve |
| Elimination Half Life (T1/2) | Day 1 to Day 63 | To assess pharmacokinetic parameters |
Countries
Argentina
Participant flow
Pre-assignment details
Of 112 enrolled participants, 90 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Zutrab® (Bevacizumab Richmond) a single 1 mg/kg IV dose of Bevacizumab
Bevacizumab: Single-dose infusion | 29 |
| Avastin® a single 1 mg/kg IV dose of Bevacizumab
Bevacizumab: Single-dose infusion | 30 |
| Cizumab® a single 1 mg/kg IV dose of Bevacizumab
Bevacizumab: Single-dose infusion | 30 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Zutrab® (Bevacizumab Richmond) | Avastin® | Cizumab® | Total |
|---|---|---|---|---|
| Age, Customized 21 to 55 years | 29 Participants | 30 Participants | 30 Participants | 89 Participants |
| Body Mass Index (BMI) | 24.05 kg/m^2 | 24.06 kg/m^2 | 24.85 kg/m^2 | 24.32 kg/m^2 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 29 Participants | 30 Participants | 30 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 12 / 29 | 13 / 30 | 10 / 30 |
| serious Total, serious adverse events | 0 / 29 | 0 / 30 | 0 / 30 |
Outcome results
Primary
Area Under the Serum Concentration- Time Curve ob Bevacizumab (ABC0-∞)
Area under the serum concentration- time curve from time zero to infinity
Time frame: Day 1 to Day 63
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Area Under the Serum Concentration- Time Curve ob Bevacizumab (ABC0-∞) | 5374225.878 h.ng/ml | Standard Deviation 1340507.11 |
| Avastin® | Area Under the Serum Concentration- Time Curve ob Bevacizumab (ABC0-∞) | 5919875.18 h.ng/ml | Standard Deviation 1276082.3 |
| Cizumab® | Area Under the Serum Concentration- Time Curve ob Bevacizumab (ABC0-∞) | 5777584.241 h.ng/ml | Standard Deviation 1951347.4 |
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.352990% CI: [80.64, 101.47]ANOVA
p-value: 0.352990% CI: [84.8, 106.49]ANOVA
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.352990% CI: [84.17, 107.67]ANOVA
Primary
Area Under the Serum Concentration-time Curve of Bevacizumab (ABC0-t)
Area under the serum concentration-time curve from time zero to the last experimental point, will be calculated by the trapezoidal rule
Time frame: Day 1 to Day 63
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Area Under the Serum Concentration-time Curve of Bevacizumab (ABC0-t) | 5153367.55 h*ng/ml | Standard Deviation 1276468.14 |
| Avastin® | Area Under the Serum Concentration-time Curve of Bevacizumab (ABC0-t) | 5641733.72 h*ng/ml | Standard Deviation 1160626.12 |
| Cizumab® | Area Under the Serum Concentration-time Curve of Bevacizumab (ABC0-t) | 5500141.94 h*ng/ml | Standard Deviation 1849362.76 |
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.361790% CI: [81.21, 101.57]ANOVA
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.361790% CI: [84.91, 105.99]ANOVA
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.361790% CI: [84.82, 108.05]ANOVA
Primary
Peak Serum Concentration of Bevacizumab (Cmax)
Cmax will be obtained directly from the serum concentration-time curve
Time frame: 0, 0.33, 0.5, 1, 1.5 hours during infusion, 0.33, 0.66, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512 hours post-infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Peak Serum Concentration of Bevacizumab (Cmax) | 22144.83 ng/ml | Standard Deviation 5550.07 |
| Avastin® | Peak Serum Concentration of Bevacizumab (Cmax) | 21540 ng/ml | Standard Deviation 4382 |
| Cizumab® | Peak Serum Concentration of Bevacizumab (Cmax) | 22566.67 ng/ml | Standard Deviation 8368.14 |
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.976690% CI: [90.19, 114.34]ANOVA
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.976690% CI: [89.75, 113.55]ANOVA
Comparison: The null hypothesis (H0) of ANOVA is that there is no difference among group means. The alternate hypothesis (H1) is that at least one group differs significantly from the overall mean of the dependent variable.p-value: 0.976690% CI: [88.16, 114.77]ANOVA
Secondary
Distribution Volume
To assess pharmacokinetic parameters
Time frame: Day 1 to Day 63
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Distribution Volume | 99.10 ml/kg | Standard Deviation 51.39 |
| Avastin® | Distribution Volume | 85.35 ml/kg | Standard Deviation 17.62 |
| Cizumab® | Distribution Volume | 97.91 ml/kg | Standard Deviation 67.17 |
Secondary
Elimination Half Life (T1/2)
To assess pharmacokinetic parameters
Time frame: Day 1 to Day 63
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Elimination Half Life (T1/2) | 352.19 h | Standard Deviation 173.17 |
| Avastin® | Elimination Half Life (T1/2) | 344.58 h | Standard Deviation 82.04 |
| Cizumab® | Elimination Half Life (T1/2) | 371.86 h | Standard Deviation 315.65 |
Secondary
Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection
To assess the immunogenic potential of the products under investigation, samples were taken for the determination of anti-bevacizumab serum antibodies for each randomized volunteer subject.
Time frame: Screening and end of study (Day 63)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | Screening | 0 participants tested positive for ADA |
| Zutrab® (Bevacizumab Richmond) | Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | End of study | 0 participants tested positive for ADA |
| Avastin® | Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | Screening | 0 participants tested positive for ADA |
| Avastin® | Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | End of study | 0 participants tested positive for ADA |
| Cizumab® | Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | Screening | 1 participants tested positive for ADA |
| Cizumab® | Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | End of study | 0 participants tested positive for ADA |
Secondary
Systemic Clearance (CL)
To assess pharmacokinetic parameters
Time frame: Day 1 to Day 63
Population: To asses pharmacokinetic parameters
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Systemic Clearance (CL) | 0.20 ml/h/kg | Standard Deviation 0.05 |
| Avastin® | Systemic Clearance (CL) | 0.18 ml/h/kg | Standard Deviation 0.04 |
| Cizumab® | Systemic Clearance (CL) | 0.19 ml/h/kg | Standard Deviation 0.06 |
Secondary
Terminal Elimination Rate Constant (λz)
Terminal elimination rate constant will be calculated by linear regression analysis of the semi-logarithmic curve
Time frame: Day 1 to Day 63
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Terminal Elimination Rate Constant (λz) | 0.002 1/h | Standard Deviation 0.001 |
| Avastin® | Terminal Elimination Rate Constant (λz) | 0.002 1/h | Standard Deviation 0.001 |
| Cizumab® | Terminal Elimination Rate Constant (λz) | 0.002 1/h | Standard Deviation 0.001 |
Secondary
Time to Reach the Peak Serum Concentration (Tmax)
Time to reach the peak serum concentration, which will be obtained directly from the serum concentration curve- time
Time frame: Day 1 to Day 63
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zutrab® (Bevacizumab Richmond) | Time to Reach the Peak Serum Concentration (Tmax) | 9.34 h | Standard Deviation 11.65 |
| Avastin® | Time to Reach the Peak Serum Concentration (Tmax) | 16.69 h | Standard Deviation 22.79 |
| Cizumab® | Time to Reach the Peak Serum Concentration (Tmax) | 5.64 h | Standard Deviation 7.46 |