Pharmacokinetics of a New Oral Formulation of Cyclosporine in Liver Transplant Recipients

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Abstract
Trough concentrations of cyclosporine can be highly variable because of its poor bioavailability in current oral formulations, Sandimmune (SIM). Neoral (N-SIM) a new microemulsion of cyclosporine is more readily absorbed than SIM in healthy controls. The present study compared the pharmacokinetic profiles of SIM and N-SIM following orthotopic liver transplantation. In 16 patients with partial biliary diversion, 1 week after transplantation, the bioavailability and peak concentration of a single 300 mg dose of N-SIM were greater than SIM by 724% (p = 0.0019) and 800% (p = 0.0001), respectively. In 39 patients who were on stable doses of cyclosporine 1 month after transplantation, the bioavailability of N-SIM was higher than that of SIM under both fasting ( + 64%, p = 0.001) and fed ( + 37%, p = 0.004) conditions. Trough concentrations were similar for the two formulations. However, peak concentrations were higher for N-SIM in both fasting ( + 119%, p = 0.003) and fed ( + 53%, p = 0.003) patients. Also, time to peak was shorter for N-SIM in both fasting (-21%, p = 0.027) and fed (-59%, p = 0.0001) patients. The correlation between trough concentrations and bioavailability was greater for N-SIM than for SIM in fasted (r = 0.80, p = 0.0001 versus r = 0.75, p = 0.0001) and fed patients (r = 0.65; p = 0.002 versus r = 0.55; p = 0.012). We conclude that the rate of absorption and the bioavailability of N-SIM is significantly and consistently better than SIM and-may, therefore, improve the therapeutic index of cyclosporine after liver transplantation.

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