Higher exposure to mycophenolic acid with sirolimus than with cyclosporine cotreatment.
BACKGROUND
Therapeutic drug monitoring of mycophenolate mofetil is recommended because of the interindividual variability in the exposition to its active moiety, mycophenolic acid. However, most of the pharmacokinetic studies involved patients cotreated with cyclosporine (INN, ciclosporin).


METHODS
We analyzed the pharmacokinetics of mycophenolic acid in 13 renal graft recipients treated with sirolimus in an anticalcineurin-free regimen and compared it with that of 17 patients cotreated with cyclosporine. The area under the concentration versus time curve over a 12-hour period (AUC 0-12 ) of mycophenolic acid was estimated at 2 weeks, 1 month, 2 months, and 3 months after transplantation.


RESULTS
At the first 3 time points, patients cotreated with sirolimus had significantly higher mycophenolic acid AUC 0-12 values compared with patients cotreated with cyclosporine, as follows: 81 mg . h/L (SD, 39 mg . h/L) versus 43 mg . h/L (SD, 11 mg . h/L) (P < .001), 72 mg . h/L (SD, 17 mg . h/L) versus 48 mg . h/L (SD, 13 mg . h/L) (P < .001), and 70 mg . h/L (SD, 25 mg . h/L) versus 47 mg . h/L (SD, 17 mg . h/L) (P < .01) at week 2, month 1, and month 2, respectively. At all time points, patients cotreated with sirolimus had significantly higher dose-normalized mycophenolic acid AUC 0-12 values. At months 1 and 2, white blood cell counts were lower in the sirolimus group than in the cyclosporine group, as follows: 4.8 x 10(3)/mL (SD, 1.1 x 10(3)/mL) versus 6.5 x 10(3)/mL (SD, 2.2 x 10(3)/mL) (P < .01) at month 1 and 4.6 x 10(3)/mL (SD, 1.1 x 10(3)/mL) versus 5.9 x 10(3)/mL (SD, 2.0 x 10(3)/mL) (P < .05) at month 2.


CONCLUSIONS
These data show that exposure to mycophenolic acid is higher in patients cotreated with sirolimus than in those cotreated with cyclosporine.
Department of Nephrology, Tours University Hospital, 37044 Tours, France. buchler@med.univ-tours.fr
Matthias
M
Büchler
Yvon
Y
Lebranchu
Maud
M
Bénéton
Yann
Y
Le Meur
Anne Elisabeth
AE
Heng
Pierre François
PF
Westeel
Chantal
C
le Guellec
Frédéric
F
Libert
Lionel
L
Hary
Pierre
P
Marquet
Gilles
G
Paintaud
D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D017248:Enzyme Multiplied Immunoassay Technique; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016030:Kidney Transplantation; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018579:Patient Selection; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013997:Time Factors
D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus