The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p< 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0but not C2or C6were associated with the risk of acute lung allograft rejection.