Improving the oral absorption of cyclosporine in malabsorbers: a review of the neoral compassionate need program

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ALTHOUGH cyclosporine is the cornerstone of transplant immunosuppression, certain patient subpopulations have not derived full clinical benefit due to suboptimal absorption from the conventional formulation, Sandimmune. Specifically in the area of kidney transplantation, variable oral absorption of cyclosporine has been identified as a biopharmaceutical risk factor for chronic allograft rejection. Across several transplant indications, characteristics associated with poor or variable absorption have been identified. Given the dependence of cyclosporine solubilization on the presence of bile in the gastrointestinal tract, cholestasis and biliary diversion in liver transplantation often necessitates the use of intravenous cyclosporine for the first postoperative days or weeks until more reliable oral absorption is established. Cystic fibrosis and diabetes are frequent comorbidities in heart-lung and kidney-pancreas transplant patients; decreased pancreatic exocrine secretions, diabetic gastroparesis, and gastrointestinal neuropathy associated with these diseases may contribute to poor systemic absorption of cyclosporine posttransplant. Decreased intestinal length and diarrhea can also impair the absorption of cyclosporine from Sandimmune in small bowel transplantation and in pediatric transplant patients in general, regardless of the transplanted organ. Neoral, a cyclosporine microemulsion, was developed in part to overcome these absorption problems by incorporating the drug in a microemulsion preconcentrate that immediately forms a microemulsion in situ upon contact with the aqueous gastrointestinal environment. Prior to its regulatory approval, a compassionate need program was conducted from 1993 to 1996 in advance of local licensing to assess the acute tolerability, safety and pharmacokinetics of Neoral. Enrolled in this open-label, international study were patients who needed very high doses of Sandimmune (.10 mg/kg per day) or who did not achieve a therapeutically acceptable trough concentration despite significant dose increases. They were converted on a milligram-tomilligram basis to Neoral with subsequent dose adjustments as necessary. Short-term safety and tolerability were assessed in all patients, and pharmacokinetic profiles were obtained in a subset. The purpose of this communication is to summarize the experience from this study across a wide variety of transplant indications in this particularly challenging group of cyclosporine malabsorbers on Sandimmune.