title: Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients.
abstract: Pharmacokinetic monitoring of CNI is unsatisfactory, because at comparable CNI blood concentrations frequency and severity of adverse effects vary considerably among individual patients. Determining the RGE of NFAT-regulated genes in leukocytes is a new pharmacodynamic approach to measure directly the functional consequences of calcineurin inhibition in T-lymphocytes. We compared clinical outcome parameters and RGE of activated T-cells after pLtx. We measured prospectively RGE of NFAT regulated genes in 33 pLTX recipients in the maintenance period after pLTX. CsA-treated patients with recurrent infections had significantly lower RGE rates (27%) than children without recurrent infections (50%; p = 0.04), whereas pharmacokinetic parameters of CsA and the concomitant immunosuppressive therapy were comparable between both groups. In patients on tacrolimus-based IS therapy NFAT RGE was only slightly reduced (90%). Pharmacodynamic monitoring of CsA by measurement of RGE in T-lymphocytes has the potential to identify over-immunosuppressed pediatric liver transplant recipients on a CsA-based IS therapy, while in children on low-dose tacrolimus therapy, RGE measurement does not provide additional clinically useful information.
authors.affiliation: Department of Pediatrics I, University Children's Hospital Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Billing
authors.forename: Thomas
authors.initials: T
authors.lastname: Breil
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
authors.forename: Claus Peter
authors.initials: CP
authors.lastname: Schmitt
authors.forename: Claus
authors.initials: C
authors.lastname: Schmitt
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Guido
authors.initials: G
authors.lastname: Engelmann
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000009:adverse effects* / Q000493:pharmacokinetics; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D007239:Infections / Q000139:chemically induced; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D016031:Liver Transplantation; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000009:adverse effects* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine; D016559:Tacrolimus