title: Reduced inter- 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.
abstract: This cross-over study compared the pharmacokinetic parameters obtained from cyclosporine (CsA) concentration-time profiles after administration of the corn oil-based soft gel cap (CsA-GC) with those with the microemulsion (CsA-ME) gel cap. Neither the fasting state nor the coadministration of a low- or high-fat breakfast affected the pharmacokinetics of CsA presented in either formulation. Comparisons of the three sets of pharmacokinetic parameters--namely, after fasting or after low-fat or after high-fat diets--demonstrated the CsA-ME formulation to display greater intraindividual reproducibility of the C0 and C12 trough levels (TLs), Cmax, tmax, and area under the concentration-time curve (AUC) than the CsA-GC formulation. Although the degree of interindividual variation in AUC, Cmax and tmax after CsA-ME administration was slightly, but significantly, less than after CsA-GC administration, there was no difference between the two formulations in terms of the customarily monitored C0 or C12 TL values. CsA-ME showed higher correlation coefficients of drug exposure (AUC) with C12 than CsA-GC (0.910 versus 0.712). However, CsA-ME administration resulted in only modest improvement over CsA-GC administration in the relationships between drug dose and C0, C12, or AUC--namely, 0.645 versus 0.496, 0.611 versus 0.517, and 0.700 versus 0.501, respectively. Correlation analysis between individual timed samples and AUC determinations revealed that CsA-ME requires significantly less frequent blood monitoring for prediction of total drug exposure than does CsA-GC. Although the clinical utility of this reproducible pharmacokinetic behavior remains to be demonstrated in the de novo transplant setting, the markedly reduced intraindividual variation produced by administration of CsA-ME will likely improve the accuracy of pretransplant prediction of, and reduce the frequency of subsequent adjustments in, CsA doses.
authors.affiliation: Division of Immunology and Organ Transplantation, University of Texas Medical School, Houston 77030.
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
authors.forename: J
authors.initials: J
authors.lastname: Dunn
authors.forename: C
authors.initials: C
authors.lastname: Fitts
authors.forename: D
authors.initials: D
authors.lastname: Van Buren
authors.forename: D
authors.initials: D
authors.lastname: Wombolt
authors.forename: R
authors.initials: R
authors.lastname: Pollak
authors.forename: R
authors.initials: R
authors.lastname: Carson
authors.forename: J W
authors.initials: JW
authors.lastname: Alexander
authors.forename: M
authors.initials: M
authors.lastname: Choc
authors.forename: R
authors.initials: R
authors.lastname: Wong
mesh_terms: D003314:Corn Oil / Q000008:administration & dosage; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D018752:Diet, Fat-Restricted; D004041:Dietary Fats / Q000008:administration & dosage; D005215:Fasting; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D016030:Kidney Transplantation; D011379:Prognosis
chemical_list: D004041:Dietary Fats; D003314:Corn Oil; D016572:Cyclosporine