title: The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic Acid in pediatric renal transplant recipients: a report of the german study group on mycophenolate mofetil therapy.
abstract: It is currently being debated whether pharmacokinetic monitoring of mycophenolic acid (MPA), the active constituent of mycophenolate mofetil (MMF), can optimize MMF therapy after organ transplantation. This open-label longitudinal study in pediatric renal transplant recipients was designed to investigate the pharmacokinetic (PK)/pharmacodynamic relationship of total and free MPA and to establish PK values for the assessment of an individual's MPA PK parameters. Fifty-four children, aged 2.2 to 17.8 yr, on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and MMF (600 mg/m(2) body surface area twice daily) were investigated 1 wk and 3 wk (initial phase) and 3 mo and 6 mo (stable phase) after renal transplantation. MPA was measured by reverse phase HPLC, free MPA by HPLC after separation by ultrafiltration. There was an association between the risk of acute rejection episodes and MPA-AUC(0-12) values or MPA predose levels; by receiver operating characteristic analysis, an AUC(0-12) of 33.8 mg x h/L in the initial phase posttransplant had a diagnostic sensitivity of 75% and a diagnostic specificity of 64% for discrimination of patients with acute rejections. The respective discrimination threshold for the MPA predose concentration was 1.2 mg/L with a sensitivity of 83% and a specificity of 64%. In contrast, high free, but not total, MPA-AUC(0-12) values were associated with an increased risk of the MMF-related side effects leukopenia and/or infections. These data indicate that therapeutic drug monitoring of MPA has the potential for optimization of MMF efficacy in this patient population by steering patients away from the low values of MPA PK variables that are associated with an increased rejection risk. For the assessment of the toxic risk of MMF regarding leukopenia and/or infections, measurement of free MPA appears to be more appropriate.
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Lutz T
authors.initials: LT
authors.lastname: Weber
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Armstrong
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Wagner
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schütz
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Otto
authors.initials: O
authors.lastname: Mehls
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Lothar B
authors.initials: LB
authors.lastname: Zimmerhackl
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.affiliation: *Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Clinical Chemistry, Georg-August University, Göttingen, Germany; and University Children's Hospital Freiburg, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
mesh_terms: D000208:Acute Disease; D002648:Child; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007239:Infections / Q000139:chemically induced; D016030:Kidney Transplantation; D007970:Leukopenia / Q000139:chemically induced; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid