T-cell function monitoring in stable renal transplant patients treated with sirolimus monotherapy.
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.
Brunet
Mercè
M
Laboratorio de Farmacología, Centre de Diagnòstic Biomèdic, IDIBAPS, Hospital Clínic, Barcelona University, Barcelona, Spain. mbrunet@clinic.ub.es
Campistol
Josep M
JM
Diekmann
Fritz
F
Guillen
David
D
Millán
Olga
O
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
D016207:Cytokines; D007166:Immunosuppressive Agents; D000255:Adenosine Triphosphate; D020123:Sirolimus
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