CONCENTRATION-GUIDED STRATEGIES IN DRUG DEVELOPMENT - EXPERIENCE WITHA CYCLOSPORINE ANALOG IN TRANSPLANTATION

A concentration-guided study was designed to maintain adequate immunos uppression and avoid excessive drug exposure while determining steady- state relative bioavailability of two cyclosporine G (CyG) oral formul ations in stable renal transplant patients. In period I (week 1), 26 p atients taking cyclosporine A (CyA)-based immunosuppressive regimens e ntered the study. Doses were titrated to maintain trough concentration s within a predefined range, as measured by fluorescence polarization immunoassay (FPIA). Patients were given an oral solution of CyG in per iod II (weeks 2-3), and a microemulsion capsule formulation of CyG in period III (weeks 4-5), with dose titration as necessary to achieve tr ough concentrations in a predefined range, as measured by FPIA, Full p harmacokinetic profiles were obtained on the last day of each study pe riod. Treatment with CyA was reinitiated in period IV (week 6) at the same doses as at study entry. All blood samples were analyzed at the c onclusion of the study using CyG- and CyA-specific high-performance li quid chromatography (HPLC). When changing from oral solution to capsul e for CyG, an average 19% dose reduction was necessary to compensate f or the elevated trough concentrations resulting from the increased bio availability of the capsule formulation. The concentration-guided stra tegy was successful in avoiding over-exposure, and resulted in compara ble values for area under the concentration-time curve (AUC) for both formulations of CyG. Dose normalization of the pharmacokinetic paramet ers subsequently allowed calculation of the relative bioavailability. Specifically a faster rate and greater extent of CyG absorption from t he capsule than the oral solution were manifested as a slightly earlie r time to peak concentration (t(max)), an average 44% increase in the maximum concentration (C-max), and an average 29% increase in AUC. Thi s experience demonstrated that a concentration-guided trial design all owed a drug development question for a compound with a narrow therapeu tic index to be addressed safely and directly in the target patient po pulation.