PHARMACOKINETICS OF THE CONVENTIONAL AND MICROEMULSION FORMULATIONS OF CYCLOSPORINE IN PANCREAS-KIDNEY TRANSPLANT RECIPIENTS WITH GASTROPARESIS

Cyclosporine (CsA) is an immunosuppressive drug requiring dose individ ualization and regular control due to its highly variable pharmacokine tics. Since gastroparesis may influence the absorption of CsA, a rando mized cross-over study was performed to assess the pharmacokinetics an d tolerability of a novel microemulsion CsA formulation in comparison with the standard CsA dosage form in six stable pancreas-kidney transp lant recipients with scintigraphically proven gastroparesis. The absor ption of CsA was investigated during three 2-hr study days during each treatment period, and a full pharmacokinetic profile was done for eac h formulation. No adverse events or differences in tolerability/safety parameters between the treatments were found. The average AUC(0-->2 h p) was 150% higher after the novel formulation, The coefficient of var iation in AUC(0-->2 hr) for both formulations was comparable (37% afte r the microemulsion and 40% after the standard formulation). The media n time at which blood CsA levels exceeded the preceding trough level b y 20% was 30 min (range: 29-182 min) after the microemulsion and 90 mi n (range: 30->718 min) after the standard formulation. With approximat ely the same average dose, the AUC(tau)(ss) after the microemulsion wa s 81% higher than the standard formulation, while predose and 12-hr tr ough levels were similar. The average maximal CsA plasma level after t he microemulsion was 396 ng/ml (95%CI: 71-722 ng/ml) higher than after the standard formulation. The median time at which the highest blood levels were observed was 90 min (range: 62-208 min) after the microemu lsion and 225 min (range: 150->718 min) after the standard formulation . The time profiles of the CsA metabolites followed those of the paren t compound. The microemulsion resulted in a higher systemic exposure t o CsA than the standard formulation in pancreas-kidney transplant pati ents with diabetic gastroparesis, but substantial variability in blood concentrations remained.