REDUCED INTERSUBJECT AND INTRASUBJECT VARIABILITY IN CYCLOSPORINE PHARMACOKINETICS IN RENAL-TRANSPLANT RECIPIENTS TREATED WITH A MICROEMULSION FORMULATION IN CONJUNCTION WITH FASTING, LOW-FAT MEALS, OR HIGH-FAT MEALS

This cross-over study compared the pharmacokinetic parameters obtained from cyclosporine (CsA) concentration-time profiles after administrat ion of the corn oil-based soft gel cap (CsA-GC) with those with the mi croemulsion (CsA-ME) gel cap. Neither the fasting state nor the coadmi nistration of a low- or high-fat breakfast affected the pharmacokineti cs of CsA presented in either formulation. Comparisons of the three se ts of pharmacokinetic parameters-namely, after fasting or after low-fa t or after high-fat diets-demonstrated the CsA-ME formulation to displ ay greater intraindividual reproducibility of the C-0 and C-12 trough levels (TLs), C-max t(max) and area under the concentration-time curve (AUG) than the CsA-GC formulation. Although the degree of interindivi dual variation in AUG, C-max and t(max) after CsA-ME administration wa s slightly, but significantly, less than after CsA-GC administration, there was no difference between the two formulations in terms of the c ustomarily monitored C-0 or C-12 TL values. CsA-ME showed higher corre lation coefficients of drug exposure (AUG) with C-12 than CsA-GC (0.91 0 versus 0.712). However, CsA-ME administration resulted in only modes t improvement over CsA-GC administration in the relationships between drug dose and C-0, C-12, or AUC-namely, 0.645 versus 0.496, 0.611 vers us 0.517, and 0.700 versus 0.501, respectively. Correlation analysis b etween individual timed samples and AUC determinations revealed that C sA-ME requires significantly less frequent blood monitoring for predic tion of total drug exposure than does CsA-GC. Although the clinical ut ility of this reproducible pharmacokinetic behavior remains to be demo nstrated in the de novo transplant setting, the markedly reduced intra individual variation produced by administration of CsA-ME will likely improve the accuracy of pretransplant prediction of, and reduce the fr equency of subsequent adjustments in, CsA doses.