Pharmacokinetic Study Of Anti-vascular Endothelial Growth Factor Drug By Intravitreal Or Subretinal Injection In Vitrectomized Eyes

Objective: To investigate the pharmacokinetic characteristics and therapeutic effects of anti-vascular endothelial growth factor(VEGF)drugs in vitretomized eyes by subretinal and vitreous injection in a prospective,randomized controlled trial and animal experiment.Methods: This study was divided into two parts: the animal experiment and the clinical trial.In the animal experiment,30 New Zealand white rabbits were randomly assigned into five groups: group A was subretinal injection + silicone oil(n=6),group B was intravitreal injection + silicone oil(n=6),and group C was subretinal injection+ BSS group(n=6),group D was intravitreal injection + BSS(n=6)and group E was simple intravitreal injection(n=6).The aqueous humor samples were collected on the 1st,3rd,7th,14 th,and 28 th day after the anti-VEGF drug injection,and the rabbit eye retina was obtained on the 28 th day.Clinical trials have been registered on China Clinical Trial Registry(Registration No.: Chi CTR-OPN-17011519),and patients with proliferative diabetic retinopathy requiring vitrectomy are divided into three groups according to the intraocular tamponade and the injection site.The eyes were randomly assigned: subretinal injection + silicone oil group(n=8),intravitreal injection +silicone oil group(n=8)and vitreous cavity injection + BSS group(n=8).Ophthalmic examinations and collection of aqueous humor samples were performed o on the 1st,3rd,7th,14 th,and 28 th day after anti-VEGF drug injection.All aqueous humor and retinal samples were tested for drug concentration by enzyme-linked immunosorbent assay(ELISA)and pharmacokinetic analysis was performed.Results: The results of animal experiments showed that compared with the drug concentration at 4 weeks after vitrectomy,the aqueous humor of group A was significantly higher than that of group B(P=0.012),and the group C was significantly higher than group D(P<0.001).The retina was compared 28 days after injection,and the drug concentration in group A was significantly higher than that in group B(P=0.005),and group C was significantly higher than group D(P=0.001).The half-life of drug elimination phase in group A and group B were 5.86±0.93 days and 3.77±0.88 days,respectively,and there was a significant difference(P=0.006);the half-life in group C and group D were 11.23±5.18 days and 4.04±0.61 days,respectively,and there was also a significant difference(P=0.019).The results of clinical trials showed that the concentration of aqueous humor 4 weeks after surgery in the subretinal injection +silicone oil group was significantly higher than that in the intravitreal injection + silicone oil group(P = 0.001).The drug mean residence time of aqueous in the subretinal injection + silicone oil group was significantly longer than that in intravitreal injection + silicone oil group(P < 0.001)and vitreous cavity injection + BSS group(P < 0.001).The BCVA in subretinal injection +silicone oil group at 6 months after surgery was significantly improved compared to the baseline BCVA(P=0.025).Conclusion: For patients who requiring vitrectomy combined with antiVEGF therapy,intraoperative subretinal injection can maintain an high intraocular drug level and prolong the duration of drug action,which may be beneficial to visual recovery.