Efficacy and pharmacokinetics of intravitreal sustained release triamcinolone/5-FU codrug suspension in the treatment of experimental PVR
Purpose. Last year we described a novel method of delivering a triamcinolone acetonide (TA)/5-FU conjugate as a sustained release suspension for the treatment of PVR in a fibroblast -injection model. Herein, we evaluate the pharmacokinetics and efficacy of TA/5-FU codrug suspension in a rabbit model of PVR which more closely mimics the time course of PVR in humans. Methods. A sustained release suspension of TA/5-FU conjugate was prepared in Healon™ as an injectable system to deliver equimolar quantities of TA and 5-FU. Forty one NZW rabbits underwent lensectomy, vitrectomy and retinal diathermy to induce PVR formation. The suspension was injected into the vitreous of the right eye of experimental rabbits at the end of the vitrectomy. Control rabbits received injection of the vehicle only. Group I compared rabbits receiving 2.5 mg TA/5-FU codrug to control. Group II compared rabbits receiving 10 mg TA/5-FU codrug to control. Severity of PVR was graded clinically by two masked observers weekly for 12 weeks. The in vitro and in vivo release rate of 5-FU and TA from the codrug was measured by HPLC. Results. Severity of PVR was significantly less in the experimental group than in the control group from week 4 to week 12 (P<0.01 in Group I, P<0.05 in Group II). In Group I, by week 8 the retina remained attached in nine (90% ) of ten rabbits in the experimental group compared with only three (25%) of twelve rabbits in the control group (P<0.01); in Group II, the retina remained attached in 89% of the experimental group vs. 40% in the control group (P<0.05). In vitro and in vivo pharmacokinetic studies showed that the TA/5-FU suspension gave sustained release of active drug and maintained vitreal levels of 5-FU and TA above 10 ug/ml over the 12 week observation period. Conclusions. The intravitreal sustained release TA/5-FU codrug suspension is effective in inhibiting the progression of PVR in a rabbit model that closely resembles PVR in humans.
Yang, DCS; Khawly, JA; Hainsworth, DP; Chen, S; Ashton, P; Guo, H; Jaffe, GJ
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