Clinical development of a cyclosporine microemulsion in transplantation

Current clinical difficulties in the use of cyclosporine in transplantation are in part due to its narrow therapeutic window between effective immunosuppression and adverse events and in part due to suboptimal absorption associated with wide pharmacokinetic variability. Under the assumption that the latter aspects are largely formulation-related, a clinical development program was undertaken to compare the conventional formulation (Sandimmun) with a new microemulsion preconcentrate (Neoral). After oral administration, Neoral immediately forms a microemulsion in aqueous gastrointestinal fluids yielding a homogeneous dispersion from which cyclosporine is more readily absorbed. Single-dose crossover studies in healthy subjects were initially performed to document improved bioavailability and dose linearity, lower intrasubject pharmacokinetic variability, and reduced food effect with Neoral. In a subsequent phase of the development program, questions that could only be assessed in transplant patients at steady state were addressed in small, open-label studies under a trough concentration-guided strategy. This approach was necessary to maintain effective immunosuppression while determining appropriate and safe guidelines for converting between formulations, assessing the trough: area under the curve correlation and exploring for potential differences in metabolism. Multicenter, double-blind, randomized investigations were then performed to compare the formulations in stable and de novo transplant populations. In this context, the conversion approach, the safety/tolerability profile, and the attendant pharmacokinetic advantages of the microemulsion formulation were confirmed in larger populations under clinical conditions. It is anticipated that the more precise pharmacokinetic control possible with Neoral will provide a firmer base from which to elucidate the relationship between cyclosporine exposure and graft survival to optimize cyclosporine-based immunosuppressive regimens.