Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients

• Published in: Pediatric transplantation Vol. 16; no. 2; pp. 187 - 194
• Main Authors: Billing, Heiko, Breil, Thomas, Schmidt, Jan, Tönshoff, Burkhard, Schmitt, Claus, Giese, Thomas, Engelmann, Guido
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2012; Blackwell
• Subjects: Adolescent; Biological and medical sciences; Biomarkers - metabolism; Child; Child, Preschool; Cyclosporine - adverse effects; Cyclosporine - pharmacokinetics; Drug Monitoring - methods; Female; Gene Expression Regulation - drug effects; General aspects; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Infection - chemically induced; Interferon-gamma - metabolism; Interleukin-2 - metabolism; Liver Transplantation; Liver, biliary tract, pancreas, portal circulation, spleen; Male; Medical sciences; NFAT; NFATC Transcription Factors - metabolism; pharmacodynamic monitoring; Prospective Studies; Real-Time Polymerase Chain Reaction; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tacrolimus - adverse effects; Tacrolimus - pharmacokinetics; Young Adult; Human; Pediatrics; Pharmacodynamics; Digestive system; Liver; Gene expression; Homotransplantation; Biological activity; NFAT; Regulation(control); Treatment; Surveillance; Surgery; Transcription factor NFAT; Graft; pharmacodynamic monitoring; Child; Monitoring; Liver transplantation
• ISSN: 1397-3142; 1399-3046
• DOI: 10.1111/j.1399-3046.2012.01660.x

Billing H, Breil T, Schmidt J, Tönshoff B, Schmitt C, Giese T, Engelmann G. Pharmacodynamic monitoring by residual NFAT‐regulated gene expression in stable pediatric liver transplant recipients. Pediatr Transplantation 2012: 16: 187–194. © 2012 John Wiley & Sons A/S. :  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.