Concentrations Of Bevacizumab Research Articles

Evaluation of the effects of vitamin D analogs, bevacizumab, and radiotherapy in uveal melanoma cells

Due to the lack of a definitive effective treatment method that provides a complete cure and increases survival rates in uveal melanoma, the search for alternative treatments at the molecular level continues. In this context, we aimed to comparatively analyze the therapeutic effects of 25-hydroxyvitamin D3 (D2), 1a, 25-dihydroxyvitamin D3 (D3), bevacizumab and radiotherapy (RT) in a uveal melanoma cell line (MP41). Cytotoxicity was evaluated using XTT cell proliferation kit and Xcelligence cell analyzer system. RT dose was determined after a clonogenic assay. Annexin V/PI staining and Western blot analyses for caspase-3, -8, and -9 were performed to analyze apoptosis. Additionally, cell cycle analyses were also conducted. As a result, we found that D2 and D3 did not show cytotoxic effects, while bevacizumab and RT showed time and dose-dependent cytotoxicity. IC50 concentration of bevacizumab was 6.945 mg/mL. Radiotherapy and bevacizumab significantly reduced cell survival and induced apoptosis when administered both as monotherapy and in combination. A significant increase in caspase proteins was detected at high bevacizumab concentrations. However, the combination of bevacizumab and radiotherapy caused a substantial decrease in caspase-3, -8 and -9 expressions. No significant difference in cell cycle distribution was detected in any treatment. Our results showed that bevacizumab inhibited MP41 cell proliferation and had an additive effect when administered with RT. In conclusion, our study offers a different perspective on the treatment of uveal melanoma, and these results, when supported by animal experiments and clinical studies in the future, might be a new step in the treatment of this challenging ocular tumor.

Computer Modeling of Bevacizumab Drug Distribution after Intravitreal Injection in Rabbit and Human Eyes.

Age-related macular degeneration (AMD) is a progressive eye disease that causes loss of central vision and has no cure. Wet AMD is the late neovascular form treated with vascular endothelial growth factor (VEGF) inhibitors. VEGF is the critical driver of wet AMD. One common off-label anti-VEGF drug used in AMD treatment is bevacizumab. Experimental efforts have been made to investigate the pharmacokinetic (PK) behavior of bevacizumab in vitreous and aqueous humor. Still, the quantitative effect of elimination routes and drug concentration in the macula are not well understood. In this work, we developed two spatial models representing rabbit and human vitreous to better understand the PK behavior of bevacizumab. This study explores different cases of drug elimination and the effects of injection location on drug concentration profiles. The models are validated by comparing them with experimental data. Our results suggest that anterior elimination is dominant for bevacizumab clearance from rabbit vitreous, whereas both anterior and posterior elimination have similar importance in drug clearance from the human vitreous. Furthermore, results indicate that drug injections closer to the posterior segment of the vitreous help maintain relevant drug concentrations for longer, improving bevacizumab duration of action at the fovea, which is located at the center of the macula. The rabbit and human models predict bevacizumab concentration in the vitreous and fovea, enhancing knowledge and understanding of wet AMD treatment.

Intraperitoneal pharmacokinetics of systemic oxaliplatin, 5-fluorouracil and bevacizumab in patients with colorectal peritoneal metastases

BackgroundPeritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier. MethodsIn a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically. ResultsA total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs. ConclusionsOur findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.

Validation of an enzyme-linked immunosorbent assay test-system for bevacizumab concentration determing in biological fluids

Introduction. One of the reasons for the development of many diseases primarily malignant is the increased expression of Vascular Endothelial Growth Factor (VEGF). Bevacizumab is a drug that neutralizes the biological activity of VEGF. The molecular structure of bevacizumab is a recombinant humanized antibody. Its use reduces vascularization in the foci of increased VEGF expression which slows down tumor growth and also helps restore vision in a number of ophthalmic diseases. To determine the concentration of bevacizumab in human biological fluids a test system based on Enzyme-linked Immunosorbent Assay (ELISA) is presented.Aim. Aim of this study is the validation of this test system.Materials and methods. Blank sera of volunteers, bevacizumab solution, enzyme-linked immunosorbent assay, solid-phase sandwich ELISA kit, microplate photometer.Results and discussion. The following characteristics of the test system were determined: the lower limit of quantification is 2.0 mcg/ml, the upper calibration range is up to 200 mcg/ml, the accuracy and precision within one series and between series does not exceed 20 %, and the total error of the method – 30 %, short-term stability for samples at room temperature – 6 hours, long-term stability – 14 days at –20 °C, the ability to freeze/thaw of samples is up to three times, the ability to determine samples with a concentration above the upper calibrator after diluting in 2 times.Conclusion. The results obtained fully comply with international acceptance criteria and allow the use of the ELISA test system manufactured by LLC "Probiotek" for use in the field of clinical laboratory diagnostics.

Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series.

Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients. Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry. We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1g/g or higher compared to those with less than 1g/g. In patients with UPCR 1g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase. This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Investigating bevacizumab and its fragments sustained release from intravitreal administrated PLGA Microspheres: A modeling approach

Intravitreal administrated bevacizumab has emerged as an effective antibody for suppressing VEGF expression in age-related macular degeneration (AMD) therapy. This study discusses certain issues related to the sustained release of bevacizumab from intravitreal poly(lactic-co-glycolic acid) (PLGA) microspheres. A computational model elucidating the ocular kinetics of bevacizumab is demonstrated, wherein the release of the drug from PLGA microspheres is modeled using the Koizumi approach, complemented by an empirical model that links the kinetics of bevacizumab release to a size-dependent hydrolytic degradation of the drug-loaded polymeric microparticles. The results of the simulation were then rigorously validated against experimental data. The as-developed model proved remarkably accurate in predicting the time-concentration profiles obtained following the intravitreal injection of PLGA microspheres of significantly different sizes. Notably, the time-concentration profiles of bevacizumab in distinct ocular tissues were almost unaffected by the size of the intravitreally administered PLGA microparticles. Furthermore, the model successfully predicted the retinal concentration of bevacizumab and its fragments (e.g., ranibizumab) administrated in the form of a solution. As such, this model for drug sustained release and ocular transport holds tremendous potential for facilitating the reliable evaluation of planned anti-VEGF therapies.

Anti-angiogenic and oxidative effects of sodium benzoate at different concentrations in chorioallantoic membrane model

<b>Aim:</b> Due to the increased consumption of packaged foods, exposure to food additives is also increasing. Sodium benzoate (SB), a frequently used food additive, is generally used in alcoholic beverages, fruit, and vegetable juices, carbonated soft drinks, canned food, and various sauces. It is used to inhibit the formation of mold, yeast, and bacteria. This study was carried out to investigate the effects of SB exposure on angiogenesis and oxidant-antioxidant balance.<br /> <b>Materials & methods:</b> Three different concentrations of SB, bevacizumab, and empty pellets were prepared, placed on chorioallantoic membrane (CAM), and examined for anti-angiogenesis. Total antioxidant capacity (TAC) and total oxidant capacity (TOC) measurements were made in the albumen samples, and oxidative stress index (OSI) value was calculated.<br /> <b>Results:</b> The control group had no anti-angiogenic effect, but the bevacizumab group had a strong anti-angiogenic effect.10<sup>-3</sup> M SB had a weak anti-angiogenic effect, but 10<sup>-4</sup> M SB and 10<sup>-5</sup> M SB showed no anti-angiogenic effect. TOC levels increased with SB in a dose-dependent manner. TAC levels decreased depending on the dose in the experimental groups with SB application. OSI levels increased depending on the dose increase in SB.<br /> <b>Conclusions:</b> SB exposure caused a dose-dependent increase in oxidative stress and anti-angiogenic effect in CAM model.

Proteome Analysis of Bevacizumab Intervention in Experimental Central Retinal Vein Occlusion.

Bevacizumab is a frequently used inhibitor of vascular endothelial growth factor (VEGF) in the management of macular edema in central retinal vein occlusion (CRVO). Studying retinal protein changes in bevacizumab intervention may provide insights into mechanisms of action. In nine Danish Landrace pigs, experimental CRVO was induced in both eyes with argon laser. The right eyes received an intravitreal injection of 0.05 mL bevacizumab (n = 9), while the left control eyes received 0.05 mL saline water (NaCl). Retinal samples were collected 15 days after induced CRVO. Label-free quantification nano-liquid chromatography-tandem mass spectrometry identified 59 proteins that were regulated following bevacizumab treatment. Following bevacizumab intervention, altered levels of bevacizumab components, including the Ig gamma-1 chain C region and the Ig kappa chain C region, were observed. Changes in other significantly regulated proteins ranged between 0.58-1.73, including for the NADH-ubiquinone oxidoreductase chain (fold change = 1.73), protein-transport protein Sec24B (fold change = 1.71), glycerol kinase (fold change = 1.61), guanine-nucleotide-binding protein G(T) subunit-gamma-T1 (fold change = 0.67), and prefoldin subunit 6 (fold change = 0.58). A high retinal concentration of bevacizumab was achieved within 15 days. Changes in the additional proteins were limited, suggesting a narrow mechanism of action.

Bevacizumab Efficiently Inhibits VEGF-Associated Cellular Processes in Equine Umbilical Vein Endothelial Cells: An In Vitro Characterization.

Anti-VEGF agents were found to have clinical implications for the successful treatment of vascular-driven diseases in humans. In this study, a detailed biological characterization of bevacizumab in a variety of in vitro assays was carried out to determine the effect of bevacizumab on equine umbilical vein endothelial cells (EqUVEC). EqUVECs were harvested from umbilical cords of clinically healthy horses and exposed to different concentrations (1, 2, 4, 6, 8 mg/mL) of bevacizumab (Avastin®). Assays concerning the drug's safety (cell viability and proliferation assay) and efficacy (cell tube formation assay, cell migration assay, and Vascular endothelial growth factor (VEGF) expression) were carried out reflecting multiple cellular processes. Bevacizumab significantly decreased VEGF expression at all concentrations over a 72 h period. No cytotoxic effect of bevacizumab on EqUVECs was observed at concentrations of 4 mg/mL bevacizumab or lower. Incubated endothelial cells showed delayed tube formation and bevacizumab efficiently inhibited cell migration in a dose-dependent manner. Bevacizumab potently inhibits VEGF-induced cellular processes and could be a promising therapeutic approach in vascular-driven diseases in horses.

Development of a liquid chromatography-based versatile bioanalysis for bevacizumab based on pretreatment combining aptamer affinity purification and centrifugal ultrafiltration concentration.

We report on the development of a versatile and accurate bioanalytical method for bevacizumab using a pretreatment method combining affinity purification with anti-idiotypic DNA aptamers and centrifugal ultrafiltration concentration, followed by liquid chromatography (LC)-fluorescence analysis. An affinity purification method using Sepharose beads as an affinity support removed immunoglobulin G and a large amount of coexisting substances in the serum sample. Purified bevacizumab was separated as a single peak by conventional LC and detected fluorometrically, showing good linearity (R2 = 0.999) in the range of 5-200μg/mL, sufficient to analyze bevacizumab concentrations in the blood of bevacizumab-treated patients. By combining this purification method with a concentration method using a centrifugal filtration device that inhibits non-specific adsorption of bevacizumab, the quantitative range was reduced by a factor of 10 while showing good linearity (R2 = 0.999) in the 0.5-20μg/mL range. The developed analytical method is expected to be used not only for general bioanalysis of therapeutic mAbs in clinical settings, but also for next-generation antibody drugs that show drug efficacy at low concentrations and for analysis of trace samples.

A phase I study comparing the biosimilarity of the pharmacokinetics and safety of recombinant humanized anti-vascular endothelial growth factor monoclonal antibody injection with Avastin® in healthy Chinese male subjects

BackgroundThe biosimilar landscape for malignancies continues to grow, with several biosimilars for reference product bevacizumab currently available. Bevacizumab has been shown to be well tolerated; however, the safety of recombinant humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody injection remains unclear. This study aimed to compare the pharmacokinetics (PK), safety, and immunogenicity of recombinant humanized anti-VEGF monoclonal antibody injection to that of Avastin® in healthy Chinese male volunteers.MethodsA randomized, double-blind, single-dose, and parallel-group study was performed on 88 healthy men who randomly (1:1) received either the test drug as an intravenous infusion of 3 mg/kg or Avastin®. The primary PK parameter was area under the serum concentration-time curve (AUC) from time zero to last quantifiable concentration (AUC0–t). Secondary endpoints included maximum observed serum concentration (Cmax), AUC from 0 extrapolated to infinity (AUCinf), safety, and immunogenicity. Serum bevacizumab concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA).ResultsThe baseline characteristics were similar among the two groups. The 90% confidence interval (CI) for the geometric mean ratio of AUC0–t, Cmax and AUCinf between the test group and reference group were 91.71%–103.18%, 95.72%–107.49% and 91.03%–103.43%, respectively. These values were within the predefined bioequivalence margin of 80.00%–125.00%, demonstrating the biosimilarity of the test drug and Avastin®. Eighty-one treatment-emergent adverse events were reported, with a comparable incidence among the test group (90.91%) and the reference group (93.18%). No serious adverse events were reported. The incidence of ADA antibodies in the two groups was low and similar.ConclusionIn healthy Chinese men, PK similarity of recombinant humanized anti-VEGF monoclonal antibody injection to Avastin® was confirmed, with comparable safety and immunogenicity. Subsequent studies should investigate recombinant humanized anti-VEGF monoclonal antibody injection in patients setting.Trial registrationRegistered 08/10/2019, CTR20191923.

Perfusable Vessel-on-a-Chip for Antiangiogenic Drug Screening with Coaxial Bioprinting.

Vessel-on-a-chips, which can be used to study microscale fluid dynamics, tissue-level biological molecules delivery and intercellular communication under favorable three-dimensional (3D) extracellular matrix microenvironment, are increasingly gaining traction. However, not many of them can allow for long-term perfusion and easy observation of angiogenesis process. Since angiogenesis is necessary for the expansion of tumor, antiangiogenic drugs play a significant role in cancer treatment. In this study, we established an innovative and reliable antiangiogenic drug screening chip that was highly modularly integrated for long-term perfusion (up to 10 days depending on the hydrogel formula) and real-time monitoring. To maintain an unobstructed flow of cell-laden tubes for subsequent perfusion culture on the premise of excellent bioactivities, a polycaprolactone stent inspired by coronary artery stents was introduced to hold up the tubular lumen from the inside, while the perfusion chip was also elaborately designed to allow for convenient observation. After 3 days of perfusion screening, distinct differences in human umbilical vein endothelial cell sprouting were observed for a gradient of concentrations of bevacizumab, which pointed to the effectiveness and reliability of the drug screening perfusion system. Overall, a perfusion system for antiangiogenic drug screening was developed, which can not only conduct drug evaluation, but also be potentially useful in other vessel-mimicking scenarios in the area of tissue engineering, drug screening, pharmacokinetics, and regenerative medicine.

The dose-dependent antiangiogenic potential of apixaban: an experimental outlook

Aim: Direct oral anticoagulants (DOACs) are good alternatives to conventional medical regimens for the treatment and prevention of thromboembolism. Apixaban is one of the more popular variations of these newly developed drugs. Aside from its anticoagulant potential, possible cellular effects remain a topic for future studies. The object of this study was to investigate the possible antiangiogenic effects of apixaban in the chorioallantoic membrane (CAM) model.Method: Drug pellets were prepared at 10-4, 10-5, and 10-6 M concentrations of apixaban and were placed in the chorioallantoic membrane on the fourth day of egg incubation. On the eighth day, all vascular densities of the membranes were compared with a 10-6 M concentration of bevacizumab, which is a known monoclonal, humanized, vascular endothelial growth-factor inhibitor.Results: We find that a 10-4 M concentration of apixaban has strong antiangiogenic potential similar to that of bevacizumab. However, there was moderate antiangiogenic potential at a lower dose of apixaban (10-5 M, 10-6 M). A comparison of the higher doses of antiangiogenic potential (10-4 M concentration) with lower doses of apixaban (10-5 M, 10-6 M) revealed significant statistical differences (p < 0.05).Conclusion: Our results indicate that a high dose of apixaban has strong antiangiogenic potential. The exact mechanism of this effect remains unknown. These pilot results should be confirmed with further studies to obtain an updated look at DOACs.

Microporous affinity membranes and their incorporation into microfluidic devices for monitoring of therapeutic antibodies

Control of monoclonal antibody (mAb) concentrations in serum is important for maintaining the safety and efficacy of these lifesaving therapeutics. Point-of-care (POC) quantification of therapeutic mAbs could ensure that patients have effective mAb levels without compromising safety. This work uses mimotope-functionalized microporous alumina affinity membranes in vertical flow assays for detection and quantitation of therapeutic mAbs. Selective capture of bevacizumab from 1000:1 diluted serum or plasma and binding of a fluorescently labelled anti-human IgG secondary antibody enable fluorescence-based analysis of bevacizumab at its therapeutically relevant concentration range of ∼50–300 μg/mL. The assay results in a linear relationship between the fluorescence intensity of the antibody capture spot and the bevacizumab concentration. A simple prototype microfluidic device containing these membranes allows washing, reagent additions and visualization of signal within 15 min using a total of 5 mL of fluid. The prototype devices can monitor physiologically relevant bevacizumab levels in diluted serum, and future refinements might lead to a POC device for therapeutic drug monitoring.

An in vitro study on the effect of bevacizumab on endothelial cell proliferation and VEGF concentration level in patients with hereditary hemorrhagic telangiectasia.

Previous studies have demonstrated that vascular endothelial growth factor (VEGF) is upregulated in patients with hereditary hemorrhagic telangiectasia (HHT). The use of Bevacizumab as an anti-angiogenic treatment agent seems promising. The purpose of the present in vitro study was to determine the efficacy and potential toxicity levels of bevacizumab on cell proliferation and VEGF concentrations in endothelial cells of HHT patients. In this in vitro study, endothelial cells from patients with HHT and HUVECs (control) were incubated with different concentration levels of bevacizumab (2, 4, 6, 8 or 10 mg/ml). After 24, 48 or 72 h, the cell proliferation was assessed by Alamar Blue® Assay and the VEGF levels in the cell culture supernatants were measured by VEGF-ELISA. All endothelial cells incubated with bevacizumab showed an initial decrease in cell proliferation. Cell proliferation recovered within 72 h in cell cultures incubated with concentration levels of up to 4 mg/ml bevacizumab, whereas those incubated with higher concentration levels showed a continuous decline in cell proliferation. VEGF expression decreased after 24 h in cell cultures incubated with bevacizumab concentration levels of 2 and 4 mg/ml but increased again after 48 h. Cell cultures incubated with bevacizumab concentration levels of 10 mg/ml showed a constant decline in VEGF expression without any tendency for recovery. Translating these results into daily clinical practice, the present study suggests that the intranasal submucosal injection of bevacizumab in HHT patients should not exceed a concentration level of 4 mg/ml. Overall, higher bevacizumab concentration levels not only reduce VEGF expression but pose a higher risk of toxic effects on endothelial cells as they jeopardize cell proliferation.

Development of a Lateral Flow Assay for Bevacizumab Using an Anti-Idiotype DNA Aptamer as a Capture Molecule

We developed a point-of-care testing method based on a lateral flow assay for bevacizumab, using an anti-idiotypic DNA aptamer as the capture molecule. Bevacizumab loaded onto the sample pad on the assay strip bound to the red-colored aptamer-modified gold nanoparticles (AuNPs) in the conjugation pad and then migrated into the developing zone. The AuNPs bound to bevacizumab were trapped by protein A on the test spot. In contrast, excess amounts of unreacted AuNPs on the control spot, confirming that they migrated correctly. The assay strips enabled analysis within 20 min after adding the sample, and bevacizumab was quantified by photographing the colored areas with a smartphone and analyzing the images. The assay kit was capable of quantifying bevacizumab in the range of 0–200 μg/mL in Avastin diluent and bevacizumab-spiked human serum samples. This assay method enables on-site analysis of bevacizumab concentrations with a simple operation and without special analytical apparatus.

Bevacizumab-Laden Nanofibers Simulating an Antiangiogenic Niche to Improve the Submuscular Stability of Stem Cell Engineered Cartilage.

Bone marrow stem cells (BMSCs) engineered cartilage (BEC) is prone to endochondral ossification in a submuscular environment due to the process of vascular infiltration, which limits its application in repairing tracheal cartilage defects. Bevacizumab, an antitumor drug with pronounced antiangiogenic activity, is successfully laden into a poly(L-lactide-co-caprolactone) system to prepare bevacizumab-laden nanofiber (BevNF) characterized by 5% and 10% bevacizumab concentrations. The in vitro results reveal that a sustained release of bevacizumab can be realized from BevNF, exhibiting inhibitive cytotoxicity toward human umbilical vein endothelial cells whereas non-cytotoxicity toward BMSCs-induced chondrocytes. A model is also established by encapsulating BEC within BevNF, aiming to realize an antiangiogenic niche under conditions of sustained and localized release of bevacizumab to inhibit the process of vascular invasion, resulting in the eventual stabilization of the cartilaginous phenotype and promotion of the process of cartilage maturation in the submuscular environment. These results also confirm that the chondrogenesis stability of BEC increases with an increase in the bevacizumab concentration, and 10% BevNF is sufficient to protect BEC from vascularization. This demonstrates that the use of BevNF can potentially help develop an effective strategy for regulating the submuscular stability of BEC to repair the defects formed in tracheal cartilage.

Plasma Levels of Bevacizumab and Vascular Endothelial Growth Factor After Low-Dose Bevacizumab Treatment for Retinopathy of Prematurity in Infants

Intravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant. To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP. This phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021. Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection. Plasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels. A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, -0.04; 95% CI, -0.28 to 0.20) or 4 weeks (ρ, -0.17; 95% CI, -0.41 to 0.08) after injection. Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.

Anti-VEGF Drugs Dynamics: Relevance for Clinical Practice.

Background: A drug and disease assessment model was used to evaluate the impact of different treatment regimens on intravitreal ranibizumab, bevacizumab, aflibercept, and brolucizumab concentrations and the proportion of free vascular endothelial growth factor (VEGF) to total VEGF. Methods: A time-dependent mathematical model using Wolfram Mathematica software was used. The pharmacokinetic and pharmacodynamic data for anti-VEGFs were obtained from published reports. The model simulated drug concentration after single and multiple doses of ranibizumab, bevacizumab, aflibercept, and brolucizumab, and it extrapolated time-dependent intraocular free VEGF proportion values. Various fixed treatment regimens (q4, q8, q10, q12) were simulated and evaluated as candidates for clinical utilization. Results: Our mathematical model shows good correlation between intraocular VEGF proportion values and clinical data. Simulations suggest that each anti-VEGF agent would allow for distinct treatment intervals to keep the proportion of free VEGF under threshold levels. Regimens scheduling q8 ranibizumab, q8 bevacizumab, q12 aflibercept, and q10 brolucizumab administration permit to maintain the proportion of unbound VEGF below 0.001%. Conclusions: Fixed q8 ranibizumab, q8 bevacizumab, q12 aflibercept, or q10 brolucizumab regimens may produce adequate intraocular VEGF inhibition.