Pharmacokinetic and pharmacodynamic correlations of cyclosporine therapy in stable renal transplant patients: evaluation of long-term target C(2).
We investigated the relationship between the pharmacokinetics and pharmacodynamics of cyclosporine in 15 stable renal transplant patients in order to define an effective and safe therapeutic range. The area under the curve of the first 4 h (AUC(0-4)), trough (C(0)) and 2 h (C(2)) levels showed median values of 1655 ng x h/ml, 114 ng/ml and 384 ng/ml, respectively. C(2) showed a strong correlation with AUC(0-4) (r=0.942, p=0.0005). C(0) correlated poorly with C(2) and AUC(0-4) (r=0.596, p=0.019 and r=0.538, p=0.031, respectively). Calcineurine activity (CNa) was 6.74% at 0 h and 3.90% at 2 h, representing significant reductions (82% and 89.6%, respectively; p<0.0005) compared with normal healthy controls (median basal value 37.4%). IL-2 production was 349 pg/ml at 0 h and 276.35 pg/ml at 2 h; both results were significantly lower (reductions of 44.5% and 56.1%, respectively; p=0.04 and 0.005) than the controls of 629.1 pg/ml. IFN-gamma at 2 h post-dose (8.16 UI/ml) was significantly lower (72.1% reduction, p=0.005) than in controls (29.2 UI/ml). There was a good correlation between CNa and IFN-gamma production, particularly at 2 h post-dose (r=0.537, p=0.007), and a fair correlation between CNa and IL-2 concentration (p=0.030, r=0.426). C(2) showed an inverse significant correlation with CNa (Spearman's p=0.000, r=-0.753), IL-2 (p=0.000, r=-0.725) and IFN-gamma (p=0.000, r=-0.701) production. In treated patients, the Emax inhibitory sigmoidal model showed that a C(2) of 279 ng/ml was needed to achieve a 50% inhibition (EC50) of IL-2 and INF-gamma production. The results demonstrated a significant inhibition of calcineurin activity and IL-2 and IFN-gamma production in patients receiving cyclosporine monotherapy compared to healthy controls. A median C(2) value of 384 ng/ml was associated with a good degree of inhibition of CNa and IL-2 and IFN-gamma synthesis, and the lack of rejection episodes and relevant toxicity.
Brunet
M
M
Pharmacology and Toxicology Department, Hospital Clínic, Universitat de Barcelona, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. mbrunet@clinic.ub.es
Campistol
J M
JM
Millán
O
O
Vidal
E
E
Esforzado
N
N
Rojo
I
I
Jiménez
O
O
Oppenheimer
F
F
Corbella
J
J
Martorell
J
J
D019540:Area Under Curve; D001682:Biological Availability; D019703:Calcineurin / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007371:Interferon-gamma; D016572:Cyclosporine; D019703:Calcineurin