Between-subject variability was included about the apparent total body clearance (CL) of bioavailable drug (F; CL/F), apparent volume of distribution (V/F), and Ka terms
Between-subject variability was included about the apparent total body clearance (CL) of bioavailable drug (F; CL/F), apparent volume of distribution (V/F), and Ka terms. a median half-life of 5.6 days from the vision and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was quick (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No variations Phenylephrine HCl in plasma free VEGF concentrations were apparent between the organizations 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 usually ongoing. Translational Relevance Our population PK and VEGF PD findings suggest a favorable Phenylephrine HCl ocular efficacy: systemic safety profile for ranibizumab in preterm infants. strong class=”kwd-title” Keywords: ROP, ranibizumab, pharmacokinetics, VEGF Introduction Retinopathy of prematurity (ROP) is usually a vasoproliferative disease of the developing retinal vasculature in preterm infants.1 The pathophysiology of ROP occurs in two phases: in phase 1, there is a delay in retinal blood vessel development because of the absence of the physiological hypoxic Phenylephrine HCl drive that occurs in utero, and in phase 2, the peripheral avascular retina expresses vascular endothelial growth factor (VEGF) into the vitreous.1,2 The high levels of VEGF in the vitreous induce Gpc2 pathological angiogenesis; abnormal blood vessels grow into the vitreous, and subsequent glial contraction may cause tractional retinal detachment.3 Current therapies for ROP are targeted to reduce VEGF levels in the retina and vitreous. While peripheral retinal ablation with a diode laser destroys the VEGF-producing cells,4,5 intravitreally injected anti-VEGF antibodies bind to intraocular VEGF.6,7 Ranibizumab is the only Phenylephrine HCl approved anti-VEGF agent in this population, based on the randomized, laser-controlled RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) study.8,9 Although several anti-VEGF agents, such as ranibizumab, bevacizumab, and aflibercept (the latter two used off-label) have been used for the treatment of ROP, their pharmacological properties and therefore clinical characteristics differ. In general, systemic exposure to anti-VEGF brokers is usually of concern in preterm infants, as VEGF-dependent developmental processes are underway in many organs.10C15 In a population pharmacokinetics (PK) study of intravitreal ranibizumab in adults, vitreous elimination half-life (t1/2) was calculated to be approximately nine days and intrinsic systemic elimination t1/2 was approximately two hours.16 In contrast, the mean serum t1/2 after intravitreal injection reported in another study in adults was 18.7 days for bevacizumab, 11.4 days for aflibercept, and 5.8 days for ranibizumab.17 In preterm infants, intravitreal bevacizumab was reported to have a serum t1/2 of 21 days18; the serum t1/2 for ranibizumab has not been reported. Only limited information around the VEGF pharmacodynamic (PD) effects of intravitreal anti-VEGF brokers in preterm infants is usually available. There was no systematic effect of ranibizumab on plasma VEGF as observed in the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) trial and in the RAINBOW study.9,19 RAINBOW was a randomized, open-label, controlled, multicenter study to compare the efficacy and safety of intravitreal ranibizumab with laser therapy in preterm infants with ROP. The study compared a single bilateral intravitreal dose of ranibizumab 0.1 mg, ranibizumab 0.2 mg, with laser therapy (1:1:1) at baseline.9 The study used dose modeling derived from known adult ranibizumab PK and the experience from other clinical trials to select the doses of 0.1 mg and 0.2 mg (20% and 40% of the clinically approved adult dose in neovascular age related macular degeneration [nAMD], respectively). The dose selection considered an approximate fourfold difference in the Phenylephrine HCl vitreous volume between birth and 18 years of age20,21 and the difference in apparent systemic volume of distribution in proportion to body weight. In this study, we aimed to develop a population PK model for intravitreal injections of ranibizumab in treated preterm infants with ROP. We also describe ranibizumab-related plasma free VEGF PD from ranibizumab PK and free VEGF PD assessments from the RAINBOW trial protocol. Methods A sparse sampling approach was used for PK and free VEGF PD assessments..