The long term goal of this research is to reduce toxicity and graft rejection due to dosing problems with the calcineurin inhibitors by developing a sustained release subcutaneous injectable formulation of the calcineurin inhibitor tacrolimus. Substantial inter-and intra-patient variability of tacrolimus due to genomic heterogeneity means that even frequent drug monitoring cannot eradicate rejection due to sub-therapeutic troughs, or toxicity due to unavoidable peak levels. In addition, non-adherence with the daily oral dosing regimen is a major cause of graft failure especially in adolescent patients. The potency and the long elimination half-life of tacrolimus makes it suitable for depot formulation, and pharmacokinetic modeling suggests that a formulation that could allow periodic subcutaneous dosing is feasible. We hypothesize that use of such a formulation could reduce or eliminate many of the problem of bioavailability, toxicity, and adherence. Funded by SBIR Phase I and II grants, we developed sustained release (SR) formulations for tacrolimus, measured its in vitro dissolution and demonstrated tolerability and sustained release in an in vivo model. Based on this work, we were granted an IND (No. 124601) to perform a 28-day study in six normal, healthy volunteers to assess the safety and preliminary pharmacokinetics (PK) of our proposed formulation.
The specific aims of this proposal are to manufacture clinical trial lots of SR injectable tacrolimus as described in IND 124601; to perform a clinical, first -in-human 28 day safety and PK study; to submit the safety and PK data from the 28 day trial to the FDA; and to analyze the data and plan further studies. The milestone for successful completion of this two-year Phase II work is the successful completion of a clinical trial demonstrating safety and sufficient drug release to merit proceeding to further development in pursuit of a New Drug Approval.
Hundreds of thousands of patients with transplants depend on immunosuppression for the survival of their donated organs. Chronic oral calcineurin inhibition with agents such as tacrolimus forms the mainstay of their treatment. However, maintenance of steady-state drug levels is difficult because of variable drug absorption and metabolism. This leads to plasma peaks which contribute to renal toxicity, and troughs which can lead to graft failure. A sustained-release formulation that could minimize peaks and troughs could lead to better and safer calcineurin inhibition. This approach also has obvious advantages for non-adherent populations such as children and adolescents. Funded by SBIR Phase I and II grants from the NIAID we have developed a subcutaneous injectable formulation for tacrolimus which has potential for dosing at bi-weekly or possibly monthly intervals, while reducing peak-to-trough ratios. We have confirmed sustained release and safety in animal models and performed the necessary pre-clinical work to obtain an IND from the FDA (No.124601). We propose, as described in the IND, a single dose safety and pharmacokinetic study in normal volunteers. Subsequent trials could lead to a product that improves adherence and reduces toxicity in transplant recipients.