This study of SDZ RAD was a randomized, double blind, stratified (to primary diagnosis of pancreatic insufficient cystic fibrosis and non cystic fibrosis), crossover trial designed to test the tolerability, safety, pharmacokinetics, pharmacodynamics, and metabolism of SDZ RAD in stable lung and heart/lung transplant recipients. Trial participants received two different single oral doses of SDZ RAD (0.035 and 0.1 mg/kg, up to a maximum of 2.5 and 7.5 mg respectively). There was a washout period of approximately 15 days between the two administrations of SDZ RAD. Twenty-four(24) evaluable subjects are planned for this multicenter study but Stanford stopped enrollment after 14 patients to allow other centers to contribute. Patients were monitored at several time points for safety and tolerability. After each dose a patient was observed on site for 48 hours during which several tests were routinely performed (vital signs, CBC, biochemistry, ECG, and urinalysis). Patients then returned daily as outpatients for the following 5 days. Blood samples for pharmacokinetic, pharmacodynamic, and metabolic analyses of SDZ RAD and Neoral (cyclosporine A, CsA) were taken several times during the first 24 hours and daily thereafter. This study is the first administration of SDZ RAD to human lung transplant recipients. SDZ RAD is a derivative of rapamycin bearing an additional 2-hydroxyethyl chain. This confers an increased polarity to the molecule, rendering it much more soluble in etheral solvents than rapamycin. Animal studies have shown it to have similar immunosuppressive profiles and possible a better toxicology profile than that of rapamycin in vivo, but with a greater oral bioavailability. In animal models of autoimmune disease and in allo-transplantation experiments, SDZ RAD has been shown to act in synergy with CsA. Patients with (n=3) and without (n=11) cystic fibrosis (CF) received Neoral twice daily (total daily dose of 225-800 mg) in combination with<=20mg/day of prednisone. Patients (6 males/8 females) had body weights of 59+-15kg (CF) and 79+-15 kg (Non-CF). Cmax and AUC differed 3-fold between high and low dose groups in NON-CG patients versus about 2-fold in CF patients. RAD absorption was delayed and systemic exposure reduced in the CF group compared to the Non-CF group. Both single oral doses of RAD did not affect the pharmacokinetics of CsA in Non-CF patients. RAD was well tolerated in this study. The preliminary single dose pharmacokinetics of SDZ RAD in stable lung transplant recipients without CF were similar to that reported in a previous single dose study in stable kidney transplant recipients. Further investigation of RAD pharmacokinetics especially in CF patients is warranted.
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