Pharmacodynamic approach to immunosuppressive therapies using calcineurin inhibitors and mycophenolate mofetil.
BACKGROUND
Graft survival depends on adequate immunosuppression. To evaluate the effect on the immune system of immunosuppressive therapies using calcineurin inhibitors (CNIs), several pharmacodynamic indices have been proposed to complement pharmacokinetic data. In this preliminary study we compared some of these parameters during combined immunosuppressant therapies.


METHODS
We treated 65 stable renal transplant recipients with cyclosporin A (CsA; n = 16), tacrolimus (TRL; n = 10); CsA + mycophenolate mofetil (MMF; n = 14); TRL + MMF (n = 13), and MMF (n = 12). Twelve nontreated healthy controls were also included. Calcineurin activity (CNA) in peripheral blood mononuclear cells was measured using (32)P-labeled peptide. Interleukin-2 (IL-2) and interferon-gamma production in phytohemagglutinin-activated whole blood were measured at 0 and 2 h postdose. The areas under the curves, c(min), c(max), and concentration at 2 h (c(2 h)) were also measured.


RESULTS
We found no differences in CNA between groups receiving CNIs alone or combined with MMF [median (25th-75th percentiles)]: CsA(2 h), 3.87 (3.00-6.85)% alkaline phosphatase (AP); CsA+MMF(2 h), 3.90 (1.78-5.19)% AP; TRL(2 h), 5.68 (3.02-16.00)% AP; TRL+MMF(2 h), 11.80 (4.05-14.63)% AP. In vitro IL-2 production was significantly lower in the groups receiving combined therapy than in groups receiving CNIs alone [median (25th-75th percentiles)]: CsA(2 h), 276.52 (190.41-385.25) ng/L; CsA+MMF(2 h), 166.48 (81.06-377.01) ng/L (P <0.001); TRL(2 h), 249.34 (127.48-363.50) ng/L; TRL+ MMF(2 h), 122.13 (51.02-180.00) ng/L (P <0.001). The correlations (r) between c(2 h) and CNA 2 h postdose were as follows: CsA, r = -0.74; CsA+MMF, r = -0.84; TRL, r = -0.70; TRL+ MMF, r = -0.70 (P <0.001 in all cases).


CONCLUSIONS
The measurement of CNA may be of help in following the effect on the immune system of CNI treatments, even in combined therapies, but does not reflect the additional effect of MMF. In contrast, IL-2 in vitro production reflects the effect of both MMF and CNIs.
Millán
Olga
O
Servei Immunologia, IDIBAPS, Hospital Clínic de Barcelona, 08036 Barcelona, Spain.
Brunet
Mercè
M
Campistol
Josep M
JM
Faura
Ana
A
Rojo
Isabel
I
Vidal
Elena
E
Jiménez
Olga
O
Vives
Jordi
J
Oppenheimer
Federic
F
Martorell
Jaume
J
D019703:Calcineurin / Q000097:blood; D065095:Calcineurin Inhibitors; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007371:Interferon-gamma; D019703:Calcineurin; D009173:Mycophenolic Acid