Clinical pharmacokinetics of bevacizumab in patients with solid tumors

Lu, Jianfeng; Bruno, René; Eppler, Steve; Novotny, William; Lum, Bert L.; Gaudreault, Jacques

doi:10.1007/s00280-007-0664-8

Cited by 319 publications

(257 citation statements)

References 12 publications

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“…The average half-life of serum proteins is about 1 day and even shorter for those that are freely filtered by the kidney. The half-life of aflibercept and bevacizumab, which are both molecules with Fc regions, is up to 3 weeks in systemic circulation (Lu et al 2008;Xu et al 2013). It has been established that the long persistence in systemic circulation of IgG and other Fc-conjugated proteins like aflibercept are due to their recycling and rescue from catabolic elimination by the FcRn via direct engagement of the Fc fragment (Roopenian & Akilesh 2007).…”

Section: Discussionmentioning

confidence: 99%

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Zehetner

Kralinger

Modi

et al. 2014

Acta Ophthalmologica

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ABSTRACT.Purpose: To evaluate the changes of vascular endothelial growth factor (VEGF) plasma levels after intravitreal injections of aflibercept or ranibizumab in patients with exudative age-related macular degeneration (AMD). Methods: Thirty-eight patients with exudative AMD were included in this randomised, prospective study. Nineteen patients were randomised to treatment with intravitreal aflibercept (2.0 mg) and 19 to intravitreal ranibizumab (0.5 mg). The concentration of VEGF was measured by ELISA just before the injection, after 7 days and 1 month. Twenty-two age-and sex-matched healthy patients without chorioretinal diseases served as control. Results: The median baseline plasma VEGF concentration was 61.0 pg/ml in the control group, 43.0 pg/ml in the aflibercept group and 59.0 pg/ml in the ranibizumab group (p = 0.127). Seven days after intravitreal injection of aflibercept plasma levels were significantly reduced to values below the minimum detectable dose (MDD) in 17 of 19 patients (89.5%) resulting in a median VEGF concentration of <9 pg/ml (p < 0.001). The reduction persisted throughout 1 month with values below the MDD in 5 of 19 patients (26.3%) and a median measurement of 17.0 pg/ml (p < 0.001). In patients treated with ranibizumab no significant effects could be observed with a baseline VEGF of 59.0 pg/ml, 54.0 pg/ ml at 7 days (p = 0.776) and 58.5 pg/ml at 4 weeks of follow-up (p = 0.670). Conclusion: After intravitreal aflibercept injection, the systemic VEGF levels were significantly reduced throughout the observational period of 4 weeks. No significant systemic effects of intravitreal ranibizumab on plasma VEGF were observed.

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Section: Discussionmentioning

confidence: 99%

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Zehetner

Kralinger

Modi

et al. 2014

Acta Ophthalmologica

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“…A two-compartment model with first-order elimination estimated that the volume of distribution of bevacizumab was 2.39 l for a typical female and 3.29 l for a typical male, which is about the expected normal plasma volume [25]. Studies in Cynomolgus monkeys revealed that the weekly administration of 2-3 mg/kg bevacizumab resulted in sustained serum levels of 10 -30 g/ml, which appears to be enough to suppress VEGF activity.…”

Section: Distributionmentioning

confidence: 94%

“…Patients with low serum albumin (Ͻ29 g/l) have, on average, a 29% higher clearance rate, whereas patients with higher ALP (Ͼ483 IU/L) levels have a 23% higher clearance rate. Patients with elevated AST have an approximately 10% lower bevacizumab clearance rate [25]. The clearance of bevacizumab also depends on the tumor burden.…”

Section: Eliminationmentioning

confidence: 99%

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Bevacizumab

2010

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“…24,25 However, bevacizumab was found to have pharmacokinetic variability based on sex. 26 Although sex has not appeared to affect the efficacy of VEGF-targeted therapies, 25 further research should be performed to determine the true impact of sex on toxicity.…”

Section: -419-21mentioning

confidence: 99%

Risk factors and model for predicting toxicity‐related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Kaymakcalan

Xie

Albigès

et al. 2015

Cancer

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BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity-related treatment discontinuation (TrTD) in mRCC patients treated with VEGF-targeted therapies. METHODS: The baseline characteristics, treatment outcomes, and toxicity data were collected for 936 mRCC patients receiving first-line VEGF-targeted therapy from the International Metastatic Renal Cell Carcinoma Database Consortium. A competing risk regression model was used to identify risk factors for TrTD, and it accounted for other causes as competing risks. RESULTS: Overall, 198 (23.8%) experienced TrTD. Sunitinib was the most common VEGF-targeted therapy (77%), and it was followed by sorafenib (18.4%). The median time on therapy was 7.1 months for all patients and 4.4 months for patients with TrTD. The most common toxicities leading to TrTD included fatigue, diarrhea, and mucositis. In a multivariate analysis, significant predictors for TrTD were a baseline age 60 years, a glomerular filtration rate (GFR) <30 mL/min/1.73 m 2 , a single metastatic site, and a sodium level <135 mmol/L. A risk group model was developed that used the number of patient risk factors to predict the risk of TrTD. CONCLUSIONS: In the largest series to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors for TrTD in mRCC patients receiving VEGF-targeted therapy. Based on the number of risk factors present, a model for predicting TrTD was built to be used as a tool for toxicity monitoring in clinical practice. Cancer 2016;122:411-9.

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Clinical pharmacokinetics of bevacizumab in patients with solid tumors

Abstract: The PK parameters were consistent with those of other IgG molecules. The results support dosing bevacizumab on a once every 2 weeks or once every 3 weeks dosing schedule on a mg/kg basis.

Cited by 319 publications

References 12 publications

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Bevacizumab

Risk factors and model for predicting toxicity‐related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

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