PHARMACOKINETICS OF THE CONVENTIONAL AND MICROEMULSION FORMULATIONS OF CYCLOSPORINE IN PANCREAS-KIDNEY TRANSPLANT RECIPIENTS WITH GASTROPARESIS1

Abstract

Cyclosporine (CsA) is an immunosuppressive drug requiring dose individualization and regular control due to its highly variable pharmacokinetics. Since gastroparesis may influence the absorption of CsA, a randomized cross-over study was performed to assess the pharmacokinetics and tolerability of a novel micro-emulsion CsA formulation in comparison with the standard CsA dosage form in six stable pancreas-kidney transplant recipients with scintigraphically proven gastroparesis. The absorption of CsA was investigated during three 2-hr study days during each treatment period, and a full pharmacokinetic profile was done for each formulation. No adverse events or differences in tolerability/safety parameters between the treatments were found. The average AUC(0→2 hr) was 150% higher after the noval formulation. The coefficient of variation in AUC(0→2 hr) for both formulations was comparable (37% after the microemulsion and 40% after the standard formulation). The median time at which blood CsA levels exceeded the preceding trough level by 20% was 30 min (range: 29-182 min) after the microemulsion and 90 min (range: 30->718 min) after the standard formulation. With approximately the same average dose, the AUCssτafter the microemulsion was 81% higher than the standard formulation, while predose and 12-hr through levels were similar. The average maximal CsA plasma level after the 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 microemulsion and 225 min(range: 150->718 min) after the standard formulation. The time profiles of the CsA metabolites followed those of the parent compound. The microemulsion resulted in a higher systemic exposure to CsA than the standard formulation in pancreas-kidney transplant patients with diabetic gastroparesis, but substantial variability in blood concentrations remained.