Sustained release calcineurin inhibitors for the prevention of graft rejection

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.