title: Pharmacokinetics of the conventional and microemulsion formulations of cyclosporine in pancreas-kidney transplant recipients with gastroparesis.
abstract: Cyclosporine (CsA) is an immunosuppressive drug requiring dose individualization and regular control due to its highly variable pharmacokinetics. Since gastroparesis may influence the absorption of CsA, a randomized cross-over study was performed to assess the pharmacokinetics and tolerability of a novel microemulsion CsA formulation in comparison with the standard CsA dosage form in six stable pancreas-kidney transplant recipients with scintigraphically proven gastroparesis. The absorption of CsA was investigated during three 2-hr study days during each treatment period, and a full pharmacokinetic profile was done for each formulation. No adverse events or differences in tolerability/safety parameters between the treatments were found. The average AUC (0-->2 hr) was 150% higher after the novel formulation. The coefficient of variation in AUC (0-->2 hr) for both formulations was comparable (37% after the microemulsion and 40% after the standard formulation). The median time at which blood CsA levels exceeded the preceding trough level by 20% was 30 min (range: 30 -> 718 min) after the standard formulation. With approximately the same average dose, the AUCss tau after the microemulsion was 81% higher than the standard formulation, while predose and 12-hr trough levels were similar. The average maximal CsA plasma level after the microemulsion was 396 ng/ml (95% CI: 71-722 ng/ml) higher than after the standard formulation. The median time at which the highest blood levels were observed was 90 min (range: 150 -> 718 min) after the standard formulation. The time profiles of the CsA metabolites followed those of the parent compound. The microemulsion resulted in a higher systemic exposure to CsA than the standard formulation in pancreas-kidney transplant patients with diabetic gastroparesis, but substantial variability in blood concentrations remained.
authors.affiliation: Department of Nephrology, Leiden University Hospital, The Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: van der Pijl
authors.forename: N
authors.initials: N
authors.lastname: Srivastava
authors.forename: J
authors.initials: J
authors.lastname: Denouël
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
authors.forename: R C
authors.initials: RC
authors.lastname: Schoemaker
authors.forename: F J
authors.initials: FJ
authors.lastname: van der Woude
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
mesh_terms: D000328:Adult; D001794:Blood Pressure; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004361:Drug Tolerance; D004655:Emulsions; D005260:Female; D018589:Gastroparesis / Q000209:etiology*; D006339:Heart Rate; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007668:Kidney / Q000098:blood supply; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D016035:Pancreas Transplantation / Q000379:methods*; D012039:Regional Blood Flow; D012077:Renal Artery / Q000502:physiology
chemical_list: D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine