Sustained release calcineurin inhibitors for the prevention of graft rejection

描述(申请人提供)：这项研究的长期目标是通过开发他克莫司和环孢素药物的缓释皮下注射制剂来减少由于钙调神经磷酸酶抑制剂剂量问题而引起的毒性和移植物排斥反应。患者之间和患者内部的巨大变异性意味着，即使频繁的药物监测也不能消除由于亚治疗低谷或毒性而导致的排斥反应，因为药物浓度高于必要的峰值。此外，不遵守每日口服给药方案是移植失败的主要原因，尤其是在青少年患者中。药代动力学模型表明，定期皮下给药可以减少或消除许多这样的问题。这些药物的效力和较长的消除半衰期使它们适合于仓库配方。在之前的工作中，部分通过SBIR第一阶段和第二阶段的资金支持，PI已经开发出FDA批准的用于治疗CMV视网膜炎和葡萄膜炎的缓释制剂。我们还开发了一种环孢素眼内给药制剂，在后葡萄膜炎的临床试验中被证明是有用的，这是一种环孢素的初步皮下制剂，显示出适度的缓释。我们现在已经开发了一种用于皮下注射的缓释平台技术，该技术部分由NIH SBIR资助，该技术在体内对其他药物显示了良好的效果，我们相信它可以实现钙调神经磷酸酶抑制剂的临床有用的缓释。这项建议的具体目的是：配制他克莫司(TAC)和环孢素(CsA)的缓释混悬剂；测试这些制剂的体外释放特性；测试这些制剂的体内药代动力学和动物局部安全性。在没有临床相关毒性的大鼠模型中，他克莫司(3周)或环孢素(1周)的持续释放将构成这个第一阶段项目的里程碑。每年进行50,000多例需要免疫抑制的移植手术，预计到2008年，免疫抑制药物的市场每年将达到25亿美元。因此，即使是一种只对少数患者有帮助的药物配方，也存在市场机会。因为成功的可能性很高(我们知道药物有效；我们只是改变了递送路线)，因为根据《孤儿药物法》的税收条款，临床试验的成本可以回收，而且我们以前开发过类似的产品，我们有信心，这项工作的成功完成将最终产生具有重大医疗用途的商业产品。

DESCRIPTION (provided by applicant): The long term goal of this research is to reduce toxicity and graft rejection due to dosing problems with the calcineurin inhibitors by developing sustained release subcutaneous injectable formulations for the drugs tacrolimus and cyclosporine. Substantial inter-and intra-patient variability means that even frequent drug monitoring cannot eradicate rejection due to sub-therapeutic troughs or toxicity due to higher than necessary peak levels. In addition, non-adherence with the daily oral dosing regimen is a major cause of graft failure especially in adolescent patients. Pharmacokinetic modeling suggests that periodic subcutaneous dosing can reduce or eliminate many of these problems. The potency and the long elimination half life of these drugs make them suitable for depot formulation. In previous work, supported in part through SBIR Phase 1 and 2 funding, the PI has developed sustained release formulations approved by the FDA for the treatment of CMV retinitis, and for uveitis. We have also developed an intraocular delivery formulation for cyclosporine that proved useful in clinical trials in posterior uveitis, a preliminary subcutaneous formulations of cyclosporine that demonstrated modest sustained release. We have now developed, in part with NIH SBIR funding, a platform delivery technology for subcutaneous injectable sustained release that has demonstrated promising results in vivo for other drugs, and that we believe is can achieve clinically useful sustained release for the calcineurin inhibitors. The specific aims of this proposal are: to formulate sustained release suspensions of tacrolimus (TAC) and cyclosporine (CsA); to test the in vitro release characteristics of these formulations; and to test the in vivo pharmacokinetics and the local safety of the formulations in animals. The demonstration of sustained release of tacrolimus (3 weeks) or cyclosporine (1 week) in the absence of clinically relevant toxicity in the rat model will constitute the milestones of this Phase 1 project. More than 50,000 transplants requiring immunosupression are performed annually and the market for immunosuppressive drugs is expected to reach $2.5 Billion annually by 2008. Thus there is a market opportunity, even for a drug formulation that helps only a minority of patients. Because the likelihood of success is high (we know the drugs work; we are only changing the delivery route), because the costs of clinical trials can be reclaimed under the tax provisions of the Orphan Drug Act, and because we have developed similar products before, we are confident that the successful completion of this work will culminate in a commercial product of significant medical utility.