title: T-cell function monitoring in stable renal transplant patients treated with sirolimus monotherapy.
abstract: BACKGROUND
  Sirolimus is an agent with lymphocyte-specific features similar to those of calcineurin inhibitors but with a different mechanism of action and safety profile. To optimize the use of sirolimus-based immunosuppression, further investigation of appropriate pharmacokinetic (sirolimus exposure) and pharmacodynamic (sirolimus T-cell immunomodulator effect) monitoring is required to determine personalized target concentrations.
  
  
  OBJECTIVE
  The main objective of the study was to evaluate the feasibility and reproducibility of combined pharmacokinetic and pharmacodynamic monitoring and to apply biomarkers of immunosuppression in stable kidney transplant recipients receiving sirolimus monotherapy.
  
  
  METHODS
  Fourteen renal transplant patients treated with sirolimus monotherapy (median 2 years) were included in this study. Pharmacokinetic and pharmacodynamic parameters were evaluated in each patient three times: at inclusion in the study (day 1), then again at 3 and 6 months.
  
  
  RESULTS
  The median sirolimus concentration was 11.5 ng/mL. CD4+ T-cell adenosine triphosphate (ATP) concentrations (150 ng/mL) and interleukin (IL)-10 production (50.9 ng/mL) were significantly lower in treated patients than in healthy controls (n = 95) [301 ng/mL; 278 ng/mL, respectively]. Median inhibition of T-cell proliferation was 60% (31-96%) in treated patients. Interferon-gamma and transforming growth factor-beta production was found to be similar to those in the healthy controls. Our results suggest an association between low ATP and IL-10 concentrations and the presence of infection.
  
  
  CONCLUSIONS
  The sequential measurement of these biomarkers in stable renal transplant recipients treated with monotherapy could be useful to evaluate the biological effect of sirolimus in each patient and to establish personalized therapy taking into account the individual response to the drug.
authors: Laboratorio de Farmacología, Centre de Diagnòstic Biomèdic, IDIBAPS, Hospital Clínic, Barcelona University, Barcelona, Spain. mbrunet@clinic.ub.es
authors: Mercè
authors: M
authors: Brunet
authors: Josep M
authors: JM
authors: Campistol
authors: Fritz
authors: F
authors: Diekmann
authors: David
authors: D
authors: Guillen
authors: Olga
authors: O
authors: Millán
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D000255:Adenosine Triphosphate; D020123:Sirolimus
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