Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.
BACKGROUND
Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients.


METHODS
Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months.


RESULTS
At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05).


CONCLUSIONS
Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.
Squifflet
J P
JP
Université Catholique de Louvain, Cliniques Universitaires Saint Luc, 10 Ave Hippocrate, B-1200 Brussels, Belgium.
Bäckman
L
L
Claesson
K
K
Dietl
K H
KH
Ekberg
H
H
Forsythe
J L
JL
Kunzendorf
U
U
Heemann
U
U
Land
W
W
Morales
J M
JM
Mühlbacher
F
F
Talbot
D
D
Taube
D
D
Tyden
G
G
van Hooff
J
J
Schleibner
S
S
Vanrenterghem
Y
Y
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D002102:Cadaver; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus