EVIDENCE FOR EARLIER STABILIZATION OF CYCLOSPORINE PHARMACOKINETICS IN DE-NOVO RENAL-TRANSPLANT PATIENTS RECEIVING A MICROEMULSION FORMULATION

Sequential cyclosporine pharmacokinetic assessments were performed at four centres within the context of a double-blind, multicenter clinica l trial comparing the safety and tolerability of the conventional form ulation with cyclosporine for microemulsion in de novo renal transplan t patients, The initial average daily oral dose was 9.3 mg/kg given in two divided doses every 12 hr with subsequent dose reductions individ ually titrated to maintain trough concentrations within the target the rapeutic range, Pharmacokinetic profiles were assessed at week 2, once between weeks 4-6, and at week 12 in 12 patients on the conventional formulation and 9 patients on the microemulsion, Over the study durati on, cyclosporine daily doses were comparable in both study arms and we re reduced in parallel from 9.2 to 6.9 to 4.7 mg/kg/day at the three s uccessive pharmacokinetic visits, Dose-normalized peak and area-under- the-curve (AUG) increased between the week 2 and week 4-6 assessments for both formulations, Thereafter, these parameters continued to incre ase for the conventional formulation but exhibited a high degree of wi thin-patient stability for the microemulsion between week 4-6 and week 12, Between-formulation comparisons indicated that the rate and exten t of cyclosporine absorption from the microemulsion were significantly higher over the study duration, Specifically, at week 2, 4-6 and 12, dose-normalized AUC was 49%, 63%, and 32% higher for the microemulsion , Intrasubject coefficients of variability for pharmacokinetic paramet ers of the conventional formulation ranged from 26.3% to 68.2%, Corres ponding values for the microemulsion were reduced by approximately hal f,ranging from 13.1% to 38.7%. The correlation between predose trough concentration and AUC was stronger for the microemulsion (r(2) 0.819 v s. 0.635) over the full range of systemic exposures attained throughou t the study, These results provide initial evidence that, as doses are reduced with time posttransplant, the cyclosporine dose-exposure rela tionship from the microemulsion may stabilize earlier than that from t he conventional formulation, allowing increased pharmacokinetic contro l over cyclosporine use in this critical posttransplant period.