Ranibizumab Population Pharmacokinetics and Free VEGF Pharmacodynamics in Preterm Infants With Retinopathy of Prematurity in the RAINBOW Trial

Abstract

To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

Combined intravitreal ranibizumab and zone I sparing laser ablation in infants with posterior zone I retinopathy of prematurity

“…[ 24 25 26 27 28 29 ] According to Rainbow trial, the elimination rate of ranibizumab from the eye was faster in infants when compared to adults (t 1/2 : 5.6 [infants] vs 8.6 days [adults]. [ 30 31 ] This could be due to several factors that includes structural difference in tissues, shorter vitreous diffusion pathway within smaller eye and reduced blood-retina vessel barrier function in active ROP. Kim et al .…”

Anti-VEGF (anti-vascular endothelial growth factor) treatment for central vein occlusion during breastfeeding

“…Die Ranibizumab-Konzentrationen waren höher als bei Erwachsenen, was mit dem unterschiedlichen Verhältnis des Augenvolumens zum Körpergewicht zusammenhängt. Es wurde aber keine klare Senkung der plasmafreien VEGF-Spiegel beobachtet [7]. Es gibt keine Hinweise auf eine Entwicklungsstörung der Kinder bis zum 2.…”

A systematic review and meta-analysis of preanalytical factors and methodological differences influencing the measurement of circulating vascular endothelial growth factor

“…Intra-ocular injections with anti-VEGF in the second phase of ROP seem to exert a similar therapeutic effect on the disease as the standard treatment with laser photocoagulation [ 14 – 16 ]. However, there is evidence for systemic leakage of intraocularly injected anti-VEGF [ 17 , 18 ]. In utero, fetal growth is extensive during the third trimester, which corresponds to the first months of life for infants born extremely preterm.…”

“…Thus, some concerns have been raised regarding the impact of postnatal anti-VEGF treatment in preterm infants on long-term outcomes [ 21 – 23 ]. While anti-VEGF is used in the treatment of ROP, VEGF can be used as a biomarker with the potential to predict ROP development and monitor treatment effects [ 17 , 24 , 25 ].…”