A phase I study of a 4-week course of SDZ-RAD (RAD) in quiescent cyclosporine-prednisone-treated renal transplant recipients

Background and Methods. This phase I, randomized, blinded, placebo-controll ed study assessed the safety profile and pharmacokinetics of a 4-week cours e of once-daily, sequential ascending doses (0.75, 2.5, or 7.5 mg/day) of S DZ-RAD (RAD) capsules in renal trans plant recipients on a stable regimen o f cyclosporine (CsA; Neoral(R)) and prednisone. Results. RAD displayed a similar spectrum of side effects as observed with rapamycin, namely, an increased incidence of infection associated with the augmented immunosuppression and a dose-related occurrence of thrombocytopen ia, hypercholesterolemia, and hypertriglyceridemia, particularly at the 7.5 -mg dose. The pharmacokinetic parameters of RAD showed dose proportionality , a good correlation between trough and area under the curve (AUC) concentr ations, and a moderate accumulation of 2.5-fold. The drug was absorbed with in 2 hr and displayed a 16-19-hr half-life, which is shorter than that of r apamycin, RAD reached steady state at 4 days. Preliminary kinetic-dynamic c orrelations indicate a correlation between thrombocytopenia (but not hyperl ipidemia) and AUG, as well as maximum drug concentrations, and weight-adjus ted dose. At the end of a 4-week course of simultaneous dosing, there was n o evidence of a pharmacokinetic interaction between CsA and RAD. Conclusion. This study suggests that the shorter half-life of RAD compared to rapamycin may confer the benefits of rapid attainment of steady state an d dissipation of effects upon drug cessation. Controlled, multicenter trial s are being planned to assess the impact of these features on clinical outc omes.