COMPARISON OF CONVENTIONAL ORAL CYCLOSPORINE AND CYCLOSPORINE MICROEMULSION FORMULATIONS IN CHILDREN WITH A LIVER TRANSPLANT

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Abstract
We studied 22 children (mean age: 8.42 years, range: 1.9-15.6 years) with a liver transplant to compare the pharmacokinetics of oral cyclosporine (CsA) microemulsion to the conventional formulation. The CsA treatment (mean dose: 5.9 mg/kg/day, range: 3.0-11.7 mg/kg/day) was converted 1:1 on a milligram-to-milligram basis to the microemulsion formulation. Five days after the conversion, the mean peak blood CsA concentration was higher (microemulsion: 963 ng/ml, range: 518-1864 ng/ml; conventional: 431 ng/ml, range: 98-888 ng/ml; P<0.0001) and it was reached faster (median time of peak concentration: 1.6 hr vs. 2.9 hr, range: 1.0-3.0 hr vs. 1.9-4.0 hr; P=0.0009). The absorption lasted on the average 19% longer after the conventional formulation. The area under the concentration versus time curve (AUC) was larger after the microemulsion formulation in all but one patient (P=0.001) by a mean factor of 1.80 (range: 0.72-3.04). The trough CsA level after the microemulsion formulation was more closely related to peak concentration (r2=0.86 vs. 0.45) and AUC (r2=0.84 vs. 0.47); thus, therapeutic drug monitoring may be more useful. After 6 months on the new formulation, the results for the whole group were similar, but in five children the AUC was comparable to the AUC obtained with the conventional formulation. No rejections occurred, and the liver and kidney functions remained unchanged. A 1:1 conversion can be safely performed in children, based on a 6-month follow-up. However, the total drug exposure changes in significant ways, which, on a long-term basis, may improve the immunosuppression in an underimmunosuppressed patient, but may increase the risk for dose-related adverse effects in others.