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Abstract

The inter- and intraindividual variability of cyclosporine pharmacokinetics from a microemulsion formulation were compared with the currently marketed formulation in a sequential bioreplication study. Twenty-four healthy male volunteers were randomized to receive each formulation on two separate occasions; the reference treatment was a single oral dose of 300 mg of Sandimmune and the test treatment was a single oral dose of 180 mg of Sandimmune Neoral, both given as soft gelatin capsules. Serial venous blood samples were obtained over a period of 48 h after each administration, and cyclosporine concentrations were measured in whole blood by a specific monoclonal RIA method. Between- and within-subject variabilities were quantified from the appropriate sums of squares from analysis of variance and statistically compared between formulations. Both inter- and intraindividual variation for the peak concentration, time to reach the peak, area under the curve, and terminal half-life of the test formulation were significantly reduced (p < 0.05) with two exceptions. For area under the curve between subjects (p < 0.2) and peak concentration within subjects (p < 0.1), trends toward reduced variability for the test formulation were evident. These results were further reflected in the inter- and intraindividual coefficients of variation of the pharmacokinetic parameters that ranged from 3 to 22% for the test formulation compared with 19 to 41% for the reference formulation. In comparison with the currently marketed formulation, reduced variability in the pharmacokinetics of cyclosporine following oral administration of Sandimmune Neoral provides a more predictable and consistent concentration–time profile.