Bevacizumab-Nwgd

Introduction Overview

Generic Name

bevacizumab-nwgd

Brand Name

Jobevne

Dosage Form

Injection

Drug Class

VEGF/VEGFR inhibitors

Pharmacokinetics

Pharmacokinetics of Jobevne (bevacizumab-nwgd):

Absorption:
Jobevne, administered intravenously, delivers bevacizumab directly into systemic circulation, bypassing absorption processes required for other routes. Clinical studies have established that bevacizumab exhibits linear pharmacokinetics with dose-proportional increases in serum concentration over the clinically relevant range of 1 to 20 mg/kg doses administered weekly or every 2 to 3 weeks. Reaching steady-state serum concentrations takes approximately 84 days, reflecting bevacizumab's slow clearance and long half-life.

Distribution:
The central volume of distribution (Vd) of bevacizumab averages 2.9 liters with moderate variability (22% coefficient of variation), indicating distribution primarily within the vascular and interstitial spaces. After adjusting for body weight, males tend to have a slightly larger Vd (3.2 L) compared to females (2.7 L). Bevacizumab does not extensively penetrate into tissues, consistent with characteristics of a large monoclonal antibody. It binds specifically to vascular endothelial growth factor (VEGF), which may influence distribution patterns in pathological tissues exhibiting angiogenesis.

Metabolism:
Bevacizumab is metabolized through catabolic pathways typical of IgG monoclonal antibodies, primarily via proteolytic degradation to small peptides and amino acids within cells of the reticuloendothelial system. It is not metabolized by hepatic cytochrome P450 enzymes and does not undergo significant metabolic biotransformation. This metabolic pathway reduces potential variability arising from hepatic dysfunction and limits drug interactions involving cytochrome P450 enzymes.

Elimination:
The mean clearance of bevacizumab is approximately 0.23 L/day with a coefficient of variation of 33%. Its elimination half-life averages 20 days, ranging between 11 to 50 days, contributing to the dose intervals of every 2 to 3 weeks used clinically. Factors influencing clearance include body weight, sex—with males having higher clearance—and tumor burden, where patients with higher tumor loads clear bevacizumab more rapidly. Renal and hepatic impairments have minimal documented effects on bevacizumab elimination due to protein catabolism-based clearance. These pharmacokinetic characteristics support the dosing regimens administered every 2 to 3 weeks to maintain therapeutic serum concentrations.

Dosage Forms

Dosage Forms of Jobevne:

Available Dosage Forms:
Jobevne is supplied as a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution in single-dose vials.
- Injection 100 mg/4 mL (25 mg/mL)
- Injection 400 mg/16 mL (25 mg/mL)

Dosages for Adults and Adolescents:
Dosage regimens vary according to indication and combination chemotherapy regimen:
- Metastatic colorectal cancer:
• 5 mg/kg IV every 2 weeks with bolus-IFL regimen
• 10 mg/kg IV every 2 weeks with FOLFOX4 regimen
• 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin chemotherapy after progression on prior bevacizumab treatment
- First-line non-squamous non-small cell lung cancer:
• 15 mg/kg IV every 3 weeks with carboplatin and paclitaxel
- Recurrent glioblastoma:
• 10 mg/kg IV every 2 weeks
- Metastatic renal cell carcinoma:
• 10 mg/kg IV every 2 weeks with interferon alfa
- Persistent, recurrent, or metastatic cervical cancer:
• 15 mg/kg IV every 3 weeks with paclitaxel and cisplatin or paclitaxel and topotecan
- Epithelial ovarian, fallopian tube, or primary peritoneal cancer:
• Stage III/IV following surgery: 15 mg/kg IV every 3 weeks with carboplatin and paclitaxel for 6 cycles; followed by 15 mg/kg IV every 3 weeks as single agent up to 22 cycles
• Platinum-resistant recurrent: 10 mg/kg IV every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or topotecan weekly; or 15 mg/kg every 3 weeks with topotecan every 3 weeks
• Platinum-sensitive recurrent: 15 mg/kg IV every 3 weeks with carboplatin and paclitaxel or carboplatin and gemcitabine for 6-10 cycles; followed by 15 mg/kg every 3 weeks as single agent until progression

Specific Patient Populations:
- Pediatric use: Safety and efficacy not established; bevacizumab not approved in patients under 18 years
- Geriatric patients: Pharmacokinetics similar to younger adults; increased risk for arterial thromboembolic events observed in patients ≥65 years
- Pregnancy: Use contraindicated due to risk of fetal toxicity; effective contraception recommended
- Lactation: Breastfeeding is discouraged during treatment and for 6 months after last dose

Administration:
Jobevne requires dilution prior to intravenous infusion (100 mL 0.9% sodium chloride). The first infusion should be administered over 90 minutes. If tolerated, the second infusion may be given over 60 minutes, and subsequent infusions over 30 minutes. Diluted solutions may be stored refrigerated up to 8 hours before use. Do not mix with dextrose solutions or shake the vial.

Mechanism Of Action

Jobevne (bevacizumab-nwgd) operates as a recombinant humanized monoclonal IgG1 antibody targeting vascular endothelial growth factor (VEGF), primarily VEGF-A isoforms. It binds selectively and with high affinity to VEGF, preventing interaction with its endothelial cell surface receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR). This blockade inhibits VEGF-induced receptor activation and downstream signaling cascades responsible for angiogenesis.

At the molecular level, VEGF binding to VEGFR triggers receptor dimerization and tyrosine kinase activation, promoting endothelial cell proliferation, migration, and new blood vessel formation—processes essential for tumor growth and metastasis. By neutralizing VEGF, Jobevne impedes the formation of new tumor vasculature, leading to reduced nutrient and oxygen supply to the tumor mass, ultimately inhibiting tumor growth and metastatic potential.

Cellular pathways affected by bevacizumab include attenuation of angiogenic signaling, limiting vascular permeability, and disrupting the supportive tumor microenvironment. This effect can normalize abnormal tumor vasculature, potentially enhancing delivery and efficacy of concomitant cytotoxic chemotherapy agents.

Clinical implications of Jobevne’s mechanism are evident in its anti-angiogenic activity, which is critical for treating various solid tumors where neovascularization plays a pivotal role. Its efficacy in improving progression-free and overall survival across multiple tumor types underscores the therapeutic value of targeting VEGF-mediated angiogenesis.

Compared to other VEGF inhibitors, such as small molecule tyrosine kinase inhibitors targeting VEGFR directly, Jobevne acts extracellularly by sequestering VEGF ligands. This distinct mechanism results in different pharmacodynamic and safety profiles, often favoring combination with chemotherapy due to manageable toxicity.

Extensive preclinical and clinical research supports the role of bevacizumab in modulating tumor vasculature, with xenograft models demonstrating marked reductions in microvascular density and metastatic progression following treatment. Clinical studies confirm the translation of these mechanistic insights into improved patient outcomes across diverse malignancies.

Pharmacological Actions

Inhibits binding of VEGF to VEGFR-1 and VEGFR-2 receptors on endothelial cells
Suppresses endothelial cell proliferation and migration essential for angiogenesis
Prevents neovascularization required for tumor growth and metastasis
Reduces vascular permeability, contributing to normalization of tumor vasculature
Enhances effectiveness of cytotoxic chemotherapy by improving tumor blood flow
Exerts anti-tumor effects through starvation of tumor tissue by vascular inhibition
Demonstrates immunomodulatory effects by altering tumor microenvironment
Binds specifically to VEGF-A, sparing other growth factors and receptors
Exhibits dose-dependent pharmacodynamics correlating with anti-angiogenic efficacy
Acts extracellularly, differing from small molecule VEGFR tyrosine kinase inhibitors
Induces regression of existing immature tumor blood vessels
Inhibits VEGF-induced nitric oxide and prostacyclin production, impacting vasodilation
Contributes to decreased interstitial fluid pressure within tumors
Does not directly kill tumor cells but impairs their growth environment
Potentially synergistic with other therapeutic agents targeting cancer pathways

Therapeutic Or Clinical Uses

Treatment of metastatic colorectal cancer in combination with fluorouracil-based chemotherapy
Second-line treatment of metastatic colorectal cancer following progression on prior bevacizumab therapy
First-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer with carboplatin and paclitaxel
Treatment of recurrent glioblastoma in adults
Combination therapy for metastatic renal cell carcinoma with interferon alfa
Management of persistent, recurrent, or metastatic cervical cancer in combination with chemotherapy
Treatment of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following surgical resection, with combination chemotherapy followed by maintenance monotherapy
Therapy for platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with selected chemotherapeutic agents
Treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with combination chemotherapy followed by maintenance therapy
Off-label use for targeting angiogenesis in other solid tumors as per oncologist discretion
Used in combination regimens to prolong progression-free survival and/or overall survival
Supports tumor control in metastatic disease settings limiting further spread
Part of multi-modal cancer therapy integrating chemotherapy, surgery, and other biologics
Approved for use based on biosimilarity to reference product Avastin, ensuring therapeutic equivalence
Integral in personalized oncology protocols due to targeted mechanism

Side Or Adverse Effects

Epistaxis (nosebleeds) occurring commonly (>10%)
Headache with variable severity
Hypertension, including severe and hypertensive crises
Rhinitis and nasal mucosal irritation
Proteinuria leading to potential nephrotic syndrome
Taste alterations reported by patients
Dry skin and exfoliative dermatitis manifestations
Hemorrhagic events, including severe and potentially fatal bleeding
Lacrimation disorders such as excessive tearing
Back pain and musculoskeletal discomfort
Wound healing complications and delayed surgical wound repair
Gastrointestinal perforations and fistulae, some fatal
Arterial and venous thromboembolic events including pulmonary embolism and stroke
Infusion-related reactions including hypersensitivity, wheezing, and anaphylaxis
Ovarian failure potentially leading to infertility
Congestive heart failure and left ventricular dysfunction
Neurological disorders including Posterior Reversible Encephalopathy Syndrome (PRES)
Fatigue, asthenia, and general malaise
Nausea, vomiting, diarrhea, and other gastrointestinal disturbances
Neutropenia and other hematologic alterations
Infections including sinusitis and urinary tract infections
Hyponatremia and electrolyte imbalances
Dermatologic toxicities including rash and nail disorders

Precautions

Withhold Jobevne at least 28 days prior to elective surgery and until adequate wound healing post-surgery
Avoid use in patients with active bleeding or recent significant hemoptysis
Monitor blood pressure regularly and manage hypertension appropriately
Regularly assess urine protein levels for proteinuria and renal function monitoring
Careful evaluation of risk factors for thromboembolism before and during treatment
Exercise caution in patients with a history of arterial thromboembolic events, diabetes, or advanced age
Advise on contraception for females of reproductive potential during therapy and for 6 months after last dose
Advise females regarding the risk of ovarian failure and discuss fertility preservation options
Monitor for signs of congestive heart failure and discontinue if cardiac dysfunction develops
Assess for infusion-related reactions during infusion and manage accordingly
Avoid use in patients with bowel obstruction or significant bowel involvement, especially in ovarian cancer
Use cautiously in patients with wound healing issues or necrotizing fasciitis
Reassess therapy in presence of gastrointestinal perforation or fistula formation
Monitor for neurological symptoms suggestive of PRES and discontinue therapy if diagnosed
Avoid combination with anthracycline-based chemotherapy due to increased cardiac risk
Regularly evaluate patients for signs of hemorrhage or bleeding complications
Use caution in patients with renal impairment due to increased risk of proteinuria
Pregnancy testing prior to initiation and avoidance during pregnancy
Inform patients about potential adverse reactions and instruct them to seek medical attention promptly

Warnings

Risk of gastrointestinal perforations and fistulae: serious and potentially fatal; discontinue if occurs
Surgery and wound healing complications: withhold drug prior to and after surgery until healing is adequate
Severe or fatal hemorrhage, including hemoptysis and gastrointestinal bleeding
Arterial thromboembolic events (ATE), including myocardial infarction and stroke, with increased risk in patients >65 years
Venous thromboembolic events (VTE), including pulmonary embolism, necessitating discontinuation for Grade 4 events
Severe hypertension, hypertensive crisis, and hypertensive encephalopathy require discontinuation or withholding of the drug
Posterior Reversible Encephalopathy Syndrome (PRES), a rare but serious neurological condition, mandates drug discontinuation
Renal injury and proteinuria, including nephrotic syndrome, requiring monitoring and possible therapy interruption
Infusion-related reactions ranging from mild hypersensitivity to anaphylaxis necessitating infusion rate adjustment or discontinuation
Embryo-fetal toxicity with congenital malformations observed in animal studies; potential fetal harm in humans
Ovarian failure and impaired fertility risk in female patients
Congestive heart failure, particularly in patients receiving anthracycline-based chemotherapy, requiring discontinuation
Necrotizing fasciitis observed, usually secondary to other severe adverse reactions, mandate immediate discontinuation
Use contraindicated in patients with recent significant hemoptysis
Safety of resuming therapy following severe adverse events like ATE, fistulae, or wound issues is not established
Potential for serious infections related to impaired wound healing and immunomodulatory effects

Contraindication

None explicitly stated; no formal contraindications listed in labeling
Use not recommended in patients with recent significant hemoptysis (≥1/2 teaspoon of red blood)
Avoid use in patients with active or recent gastrointestinal perforation or fistula
Contraindicated during pregnancy due to potential fetal harm (class warnings)
Use with caution in patients with unhealed wounds or high risk for wound healing complications
Avoid combination with anthracyclines given increased risk for congestive heart failure
Not indicated for pediatric patients; safety and effectiveness unestablished
Not indicated for adjuvant treatment of colon cancer due to lack of demonstrated efficacy
Avoid in patients with bowel obstruction or evidence of bowel involvement in pelvic malignancies
Use cautiously or avoid in patients with uncontrolled hypertension or cardiovascular instability
Contraindicated in patients with known hypersensitivity to bevacizumab or its components

Drug Interactions

No clinically meaningful pharmacokinetic interactions observed with irinotecan or its active metabolite SN38
No significant effect on interferon alfa pharmacokinetics when co-administered
No meaningful impact on carboplatin or paclitaxel pharmacokinetics documented; however, some patients showed reduced paclitaxel exposure after multiple cycles with bevacizumab
Potential pharmacodynamic interactions increasing risk of bleeding with anticoagulants
No known interaction with cytochrome P450 enzymes due to elimination via proteolytic catabolism
Caution advised when combining with other agents affecting blood pressure as additive hypertension may occur
No significant effect on therapeutic plasma levels of chemotherapeutic agents but concurrent toxicities should be monitored
Possible increased risk of thromboembolic events when used with agents predisposing to thrombosis
Avoid mixing or administering with dextrose-containing solutions due to incompatibility concerns
Monitor for infusion-related hypersensitivity when given with other monoclonal antibodies
No formal dose adjustments required for concomitant drug administration, but clinical monitoring advised
Potential increased nephrotoxicity when co-administered with nephrotoxic agents due to additive proteinuria
May alter wound healing when combined with agents that impair tissue repair
Immunogenicity may alter effectiveness or increase hypersensitivity risk when combined with other biologics
No documented interactions with oral contraceptives, but pregnancy prevention advised

Preparations Of The Drug

Jobevne injection is provided as a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution
Available in single-dose vials containing 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL)
Each mL contains bevacizumab-nwgd 25 mg, trehalose dihydrate 54.3 mg, polysorbate 20 0.4 mg, dibasic sodium phosphate 1.2 mg, monobasic sodium phosphate 4.5 mg, and water for injection
pH adjusted to approximately 6.2 with sodium hydroxide and phosphoric acid during manufacturing
Supplied in cartons containing one single-dose vial
Stored refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light
Do not freeze or shake the vials to maintain product integrity
Must be diluted prior to administration in 0.9% sodium chloride solution to a volume of approximately 100 mL
Diluted solutions are stable for up to 8 hours under refrigeration
Do not dilute or mix with dextrose-containing solutions
Discard any unused portion left in the vial as no preservatives are present
Preparation requires aseptic technique using sterile needles and syringes
Proper infusion procedures: first infusion over 90 minutes, second over 60 minutes if tolerated, subsequent infusions over 30 minutes
Meets biosimilarity standards to reference biologic Avastin with identical formulation and storage requirements
Product manufactured by Biocon Biologics Inc., a Biocon Biologics Company