Younghoon Yoo (1), Hwi-yeol Yun (1), Byungjeong Song (1), Hyun-moon Back (1), Siyoung Hwang (1), Eben Jung (1), Kwang-il Kwon (1) and JaeWoo Kim(2)
(1) College of Pharmacy, Chungnam National University, Daejeon, Korea, (2) Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
Objectives: Recent studies have shown that intravitreal or intracameral injection of bevacizumab, a full length anti-VEGF antibody, may be a useful adjunct in the treatment of neovascular glaucoma. One way of delivering macromolecules is subconjunctival injection. But in each eye, the concentration of bevacizumab has different conditions. Pharmacokinetic model for subconjunctival administration of bevacizumab had not been developed yet. In this study, we developed pharmacokinetic model for subconjunctival administration of bevacizumab and investigated reason of different concentration.
Methods: The right eye of 33 rabbits was injected with 2.5 mg of subconjunctival bevacizumab. Three rabbits were sacrificed at each of the following time points: 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 120, 168 h after the injection. Bevacizumab concentrations were measured in aqueous fluid of injected and un-injected eyes and serum.[1] Pharmacokinetic model of bevacizumab was developed by NONMEM(ver. 7.3). The model parameters was estimated using First-order conditional estimation and evaluated using goodness of fit (GOF) and visual predict check (VPC, n=1000).
Results: Bevacizumab was first detected in the aqueous humor of the injected eye at 12 h after the subconjunctival injection. Bevacizumab was also detected in the serum and aqueous humor of the un-injected contralateral eye. The concentration in the aqueous humor of the injected eye was lower than in the serum and higher than in the aqueous humor of the un-injected contralateral eye at all time points. Subconjunctival injection model was developed with six-compartments including subconjunctival space and each vitreous humor compartments. Serum volume of distribution(VC), absorption rate constants(ka), clearance(CL) and aqueous humor volume of distribution(VA) of this model is 0.347mL, 0.698hr-1, 286mL/hr and 3.62mL, respectively. As a result of GOF and VPC, our subconjunctival injection model was robust and parameter values were reliable.
Conclusions: We demonstrated that bevacizumab can be delivered into anterior chamber by single subconjunctival injection. Pharmacokinetic model for subconjunctival injection of bevacizumab was successfully developed and evaluated. The model was appropriate to predict the plasma and aqueous humor of each eye concentration of bevacizumab in rabbits and may be useful to develop human model with neovascular glaucoma in further study.
References:
[1] kim MJ, Han ES, Kim JW, Kim TW. Aqueous Humor Concentration of Bevacizumab After Subconjunctival Injection in Rabbit. Journal of ocular pharmacology and therapeutics(2010)26(1): 49-54
Reference: PAGE 25 (2016) Abstr 5950 [www.page-meeting.org/?abstract=5950]
Poster: Drug/Disease modeling - Other topics