Improved absorption of cyclosporine for microemulsion in a pediatric liver transplant recipient with cystic fibrosis

Cystic fibrosis, a common indication for lung transplantation, is an uncommon indication for liver transplantation. Cystic fibrosis results in cirrhosis in about 30% of patients. The biliary type of cirrhosis is characterized by fibrosis; bile duct proliferation; and, in some cases, accumulation of eosinophilic PAS-positive, diastase-resistant material in the interlobular ducts. The cirrhosis is hypothesized to result from production of lithogenic bile resulting from excessive loss of bile acids. With improvement in pulmonary care, some patients have progressed to liver failure requiring transplantation while maintaining normal pulmonary function. The results of liver transplantation in these patients are generally good with no apparent increase in morbidity. With the exception of one patient, all the reported cases of liver transplantation for cystic fibrosis have used cyclosporine (CsA) as part of the immunosuppressive protocol. The present formulation of CsA, Sandimmune, is in an olive or corn oil base. The absorption of CsA after an oral dose of Sandimmune is dependent on multiple factors, including biliary and pancreatic secretions, that are necessary to digest and emulsify the preparation. With impaired pancreatic exocrine function in cystic fibrosis, CsA absorption would be affected. Reported cases of liver transplantation in patients with cystic fibrosis have demonstrated the need for higher doses of Sandimmune to achieve adequate therapeutic CsA blood levels. A new formulation of CsA, Neoral, has recently been marketed in Europe and is under investigation in the United States. Neoral is a microemulsion containing cremophor RH40, propylene glycol, and dl- alpha -tocopherol, which act as surfactants and both lipophilic and hydrophilic solvent. The droplet size is between 10 and 100 nm in diameter. Neoral disperses upon contact with aqueous solvents independent of biliary and pancreatic secretion. In randomized trials in stable renal transplant recipients these characteristics have resulted in a higher maximum concentration (Cmax) at an earlier time (Tmax), a greater area under the concentration curve (AUC) and less inter- and intrapatient variability when compared with Sandimmune. Based on these results, a compassionate use protocol providing Neoral to solid organ transplant recipients who require high doses of Sandimmune to achieve adequate CsA trough blood levels was designed. We report here a pediatric liver transplant recipient with cystic fibro