Comparison of mycophenolic acid pharmacokinetic parameters in kidney transplant patients within the first 3 months post-transplant.
OBJECTIVE
The aim of this study was to investigate the effect of time on pharmacokinetic (PK) parameters of mycophenolic acid (MPA) in the early post-transplant period in kidney recipients. MPA is the active metabolite of mycophenolate mofetil (MMF), which was introduced into clinical practice ten years ago.


METHODS
Mycophenolate mofetil was co-administered with cyclosporin (CsA) in a subgroup of 23 patients and with tacrolimus (Tac) in a subgroup of 10 patients. MPA plasma concentration profiles were measured by a validated high performance liquid chromatography method 1 week, 2 and 3 months after transplantation.


RESULTS
Despite a comparable MMF dose, a large inter-patient variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.03-135.4 microg h/mL) and in predose concentrations (0.31-6.09 microg/mL) was observed. Patients with AUC > 35 microg h/mL showed better (P < 0.1) renal function than patients with AUC < 20 microg h/mL (mean creatinine concentration 1.48 +/- 0.12 vs. 3.35 +/- 0.4 mg/dL respectively). The total MPA trough and AUC did not correlate with biochemical parameters: leucocyte cell count and haematocrit. A higher trough level of the metabolite MPA glucuronide (MPAG) in the 1 week after transplantation was found when compared with the 3-month level (mean 150.1 +/- 146.7; range 17.1 to 560 vs. 75.8 +/- 40.0; range 27.3 to 174.2 microg/mL). The concentration of MPA, and MPA AUC values were significantly lower in patients receiving MMF and CsA than those receiving MMF and Tac during all three periods studied (P < 0.02). The influence of C(0) and MPA AUC values on the risk of graft rejection was investigated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for AUC was 0.847, whereas that of C(0) was 0.632.


CONCLUSIONS
The MPA AUC(0-12h) appeared to be the more effective PK parameter for predicting acute rejection. We recommend that routine MPA and MPAG therapeutic drug level monitoring should be an important part of MMF therapy.
Department of Drug Chemistry, Faculty of Pharmacy, Warsaw Medical University, ul. Banacha 1, PL-02097 Warsaw, Poland. tompaw@farm.amwaw.edu.pl
T
T
Pawinski
M
M
Durlik
I
I
Szlaska
A
A
Urbanowicz
J
J
Majchrnak
B
B
Gralak
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D003404:Creatinine / Q000145:classification; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D020719:Glucuronides / Q000097:blood; D006084:Graft Rejection / Q000517:prevention & control*; D006400:Hematocrit; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D013997:Time Factors
D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D003404:Creatinine; D009173:Mycophenolic Acid; D016559:Tacrolimus