Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD

Robert L Avery, Alessandro A Castellarin, Nathan C Steinle, Dilsher S Dhoot, Dante Joseph Pieramici, Robert See, Stephen Couvillion, Ma'an A Nasir, Melvin D Rabena, Kha Le, Mauricio Maia, Jennifer E Visich, Robert L Avery, Alessandro A Castellarin, Nathan C Steinle, Dilsher S Dhoot, Dante Joseph Pieramici, Robert See, Stephen Couvillion, Ma'an A Nasir, Melvin D Rabena, Kha Le, Mauricio Maia, Jennifer E Visich

Abstract

Background: Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking.

Methods: Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections.

Results: Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL.

Conclusions: There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF.

Trial registration number: NCT02118831.

Keywords: Retina.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
Serum concentration–time curves for ranibizumab, bevacizumab, or aflibercept following intravitreal injection in patients with age-related macular degeneration.
Figure 2
Figure 2
Mean (95% CI) plasma free VEGF concentration following intravitreal injection of ranibizumab, bevacizumab, or aflibercept in patients with age-related macular degeneration. VEGF, vascular endothelial growth factor.
Figure 3
Figure 3
Individual observed plasma free VEGF concentrations following intravitreal injection of ranibizumab, bevacizumab, or aflibercept. ITV, intravitreal; VEGF, vascular endothelial growth factor.

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