Improved absorption and bioavailability of cyclosporine A from a microemulsion formulation in lung transplant recipients affected with cystic fibrosis

Abstract

CLINICAL benefit of cyclosporine A (CyA) in the prevention of acute rejection in organ transplantation has been widely proven. This immunosuppressive agent is a cyclic undecapeptide of fungal origin with high lipophilicity, and oral formulations (soft gelatine capsules and solution) are based on oil and ethanol. Absorption of such a molecule occurs preferentially from the small bowel, and is affected by coadministration of food and various drugs, impaired bile flow, and small bowel function, resulting in high intra and interindividual variability of pharmacokinetics parameters. In cystic fibrosis (CF) patients the absorption of the currently available form of CyA (Sandimmun SIM, Sandoz Pharma, Ltd, Basel, Switzerland) is frequently impaired. Such patients require high doses of CyA and frequent monitoring of the blood trough levels (TL) as compared with other recipients. The recent formulation of CyA in a microemulsion preconcentrate (Neoral, Sandoz Pharma, Ltd) spontaneously forms an homogenous emulsion in the aqueous environment of the small gut. The objective of the development of Neoral was to offer an improved formulation optimally absorbed that could be of great interest particularly in malabsorbing patients. Previous clinical studies have shown the improved bioavailability of the Neoral preparation in renal transplant recipients with normal gut function 1–3 and in selected liver transplant patients where the absorption of SIM was impaired by cholestasis. 4,5 Preliminary encouraging results were obtained from CF recipients in whom bile and pancreatic enzyme secretion is impaired and variable. 6–8 The aims of the present study were to compare the steady state pharmacokinetics of CyA after conversion from SIM to an equal dose of Neoral, and to assess the tolerability and safety of Neoral in the postoperative management of CF lung and heart-lung transplant recipients.