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Clinical Trial
, 37 (10), 1847-1858

SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB

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Clinical Trial

SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB

Robert L Avery et al. Retina.

Abstract

Purpose: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO).

Methods: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections.

Results: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF.

Conclusion: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.

Figures

Fig. 1.
Fig. 1.
Mean (SD) serum concentration–time profiles of each drug after intravitreal injection with aflibercept, bevacizumab, or ranibizumab in (A) patients with AMD, (B) patients with DME, and (C) patients with RVO. The black, gray, and light gray lines represent the IC50 for bevacizumab, aflibercept, and ranibizumab, respectively. ITV, intravitreal. Figure 1A was reproduced, with permission, from Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 2014;98:1636–1641. http://bjo.bmj.com/content/98/12/1636; licensed under CC BY-NC 3.0.
Fig. 2.
Fig. 2.
Plasma levels of free-VEGF in (A) patients with AMD, (B) patients with DME, and (C) patients with RVO. Lines represent median and interquartile range. Dotted line represents the LLOQ. Outliers (>75 pg/mL) are not illustrated for better visualization of the data, but are included in the median and interquartile range (AMD: 1 level in patient treated with ranibizumab; DME: 2 levels in patients treated with bevacizumab, 5 levels in patients treated with ranibizumab; RVO: 13 levels in patients treated with bevacizumab, 6 levels in patients treated with ranibizumab). Plasma VEGF levels that measured lower than the LLOQ were assigned a value of 50% of the LLOQ. ITV, intravitreal. Figure 2A was reproduced, with permission, from Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 2014;98:1636–1641. http://bjo.bmj.com/content/98/12/1636; licensed under CC BY-NC 3.0.
Fig. 3.
Fig. 3.
Mean (95% CI) plasma free-VEGF with bevacizumab, ranibizumab, and aflibercept in (A) patients with AMD, (B) patients with DME, and (C) patients with RVO. ITV, intravitreal. Figure 3A was reproduced, with permission, from Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 2014;98:1636–1641. http://bjo.bmj.com/content/98/12/1636; licensed under CC BY-NC 3.0.

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