Conversion from liquid to solid rapamycin formulations in stable renal allograft transplant recipients

Sirolimus (rapamycin, RAPA, Rapamunetrade mark) is a potent immunosuppressive agent currently being investigated for prophylaxis against acute rejection episodes in renal transplant recipients. In the present study, stable renal allograft recipients under maintenance therapy with RAPA and cyclosporine (CsA) were converted from the original oil-based liquid RAPA to a solid tablet formulation on a milligram-to-milligram basis, in order to evaluate the pharmacokinetics and safety of this new dosage form. Twelve-hour pharmacokinetic (PK) profiles of both RAPA and CsA were conducted with the final liquid RAPA dose, and at 2, 4, and 8 weeks postconversion to the solid tablet. In addition, the parameters of the PK profiles for the solid formulation were compared with those for liquid RAPA, which were performed prior to this study. Area under the concentration-time curve (AUC) values for the liquid formulation and for the solid tablet at 2, 4, and 8 weeks postconversion were 256.5, 205.8, 226.1, and 224.4 ng.h/mL, respectively (p=NS). Time to maximum RAPA concentration was longer at 4 weeks postconversion, but similar at 2 and 8 weeks. There were no differences observed between the liquid and solid tablet trough concentrations. The only significant differences observed among the PK parameters of the solid tablet versus those of the liquid formulation were the lower C(max) values of the solid, namely 25.3, 24.9, and 26.7 ng/mL versus 37.1 ng/mL (p<0.05). In addition, the dose corrected C(max) was lower in the solid tablet PK profiles compared with the prior PK profiles for the liquid (7.7 versus 10.2 ng/mL, p<0.02). Cyclosporine AUC values did not change appreciably during the study. Conversion from the liquid to the solid formulation was neither associated with episodes of acute rejection, nor changes in laboratory values, during the 8-week study. In summary, conversion from the liquid to the solid RAPA formulation resulted in similar PK profiles and appears to be both safe and well-tolerated in renal transplant recipients.