title: Cyclosporin A absorption profiles in pediatric renal transplant recipients predict the risk of acute rejection.
abstract: The current focus of cyclosporin A (CsA) monitoring in adult transplantation for optimized immunosuppression is on the early portion of the CsA area under the concentration-time curve (AUC), particularly in the first 4 hours postdose, designated as AUC(0-4), and on the blood concentration 2 hours postdose (C2) as a highly predictive marker for AUC(0-4). Because data in pediatric patients are scarce, full-time (12 hours) and absorption profiles of CsA were analyzed in relation to CsA effectiveness in 61 pediatric renal transplant recipients aged 3.2 to 17.4 years on an immunosuppressive triple regimen with CsA, mycophenolate mofetil, and methylprednisolone. CsA dosing was based on body surface area and adjusted to CsA trough levels. Pharmacokinetic (PK) profiles were obtained 1 and 3 weeks (initial period) and 3 and 6 months posttransplant (stable period). Patients with an AUC(0-4) < 4400 microg x h/L at both PK sampling periods in the first 3 weeks posttransplant had an adjusted relative risk of 48.4% to suffer an acute rejection episode (ARE), whereas in patients with at least 1 AUC0-4 above this threshold, the adjusted relative risk for an ARE was only 13.1% (P < 0.02). The single PK parameters C0 or C2 did not discriminate between patients with and without acute rejection. The PK parameters C1.25 (r2 = 0.64) or C2 (r2 = 0.60) showed a stronger relationship to the absorption profile (AUC(0-4)) than C0 (r2 = 0.15). An abbreviated profile consisting of the PK variables C(0.5;2) or C(0;0.5;2) showed the closest correlation to the absorption profile (r2 = 0.89) and the lowest percentage prediction error. These data indicate that absorption profiling in pediatric renal transplant recipients has the potential to optimize immunosuppressive therapy with CsA.
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital, Heidelber, Germany.
authors.forename: Lutz T
authors.initials: LT
authors.lastname: Weber
authors.forename: Victor W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Reinhard
authors.initials: R
authors.lastname: Feneberg
authors.forename: Manfred
authors.initials: M
authors.lastname: Wiesel
authors.forename: Otto
authors.initials: O
authors.lastname: Mehls
authors.forename: Lothar B
authors.initials: LB
authors.lastname: Zimmerhackl
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004655:Emulsions; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008137:Longitudinal Studies; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid