title: Pharmacodynamic disparities in tacrolimus-treated patients developing cytomegalus virus viremia.
abstract: BACKGROUND
  The optimal balance between efficacy and toxicity of tacrolimus (Tac) treatment remains unsolved. The quantification of nuclear factor of activated T cell (NFAT)-regulated gene expression may provide a tool to monitor the individual susceptibility to Tac.
  
  
  METHODS
  Expression of NFAT-regulated genes (interleukin-2, interferon-gamma, and granulocyte-macrophage colony stimulating factor) in peripheral blood from renal transplant patients (N = 73) was measured by quantitative real-time polymerase chain reaction (at C0, C1.5, and C4) and correlated to clinical endpoints in a 1-year observation period. In a subgroup (n = 10), NFAT expression was quantified over a 12-hour dose interval.
  
  
  RESULTS
  Median daily Tac dose of 73 stable renal transplant patients [median age 47 years (range 19-69 years)] was 5 mg (1-13), Tac trough (C0), 1.5-hour (C1.5) and 4-hour (C4) concentrations were 8.5 mcg/L (3-20), 20 mcg/L (4.7-50.4), and 14.5 mcg/L (4.5-37.5), respectively. The mean residual expression of all 3 NFAT-regulated genes was 21% at C1.5 (1-84) and 35% at C4 (2-88). The relative reduction of gene transcripts was inversely correlated with the individual Tac blood concentrations. Seven patients had cytomegalus virus viremia during the observation period, and their residual NFAT-regulated gene expression at C1.5 was significantly lower [13% (1-21) versus 26% (1-84), P = 0.02] compared with those without viremia despite comparable Tac blood concentrations (6.3 versus 8.6 mcg/L).
  
  
  CONCLUSIONS
  Monitoring of NFAT-regulated gene expression in Tac-treated transplant recipients provides a tool to assess the individual response to Tac, identify patients at the risk of developing cytomegalus virus viremia, and may, thus, help to select the optimal Tac dose with respect to safety and toxicity.
authors: Department of Nephrology, University Hospital, Heidelberg, Germany. claudia.sommerer@med.uni-heidelberg.de
authors: Claudia
authors: C
authors: Sommerer
authors: Martin
authors: M
authors: Zeier
authors: David
authors: D
authors: Czock
authors: Paul
authors: P
authors: Schnitzler
authors: Stefan
authors: S
authors: Meuer
authors: Thomas
authors: T
authors: Giese
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000097:blood / Q000139:chemically induced* / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D016559:Tacrolimus / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D014766:Viremia / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000821:virology; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016559:Tacrolimus