Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen.
OBJECTIVE
The pharmacokinetics of both tacrolimus and mycophenolic acid in renal transplant recipients on a corticosteroid-free regimen was evaluated.


METHODS
Upon administration of steady-state morning tacrolimus and mycophenolate mofetil doses, 28 patients for whom at least three months had passed after renal transplantation underwent serial blood sample collection over a 12-hour dosing period. Whole blood concentrations of tacrolimus were measured, as were mycophenolic acid, mycophenolic acid 7-0-glucuronide (MPAG), and acyl glucuronide MPAG (AcMPAG) concentrations. Pharmacokinetic parameters were then analyzed by conventional noncompartmental modeling.


RESULTS
The mean ± S.D. pharmacokinetic parameters for tacrolimus, normalized to a dose of 1 mg, were as follows: area under the concentration-time curve (AUC), 52.6 ± 24.8 μg · hr/L/mg; maximum concentration (C(max)), 8.0 ± 3.3 μg/L/mg; time to C(max) (t(max)), 1.8 ± 1.0 hr; and minimum concentration (C(min)), 2.6 ± 1.4 μg/L/mg. The mean ± S.D. pharmacokinetic parameters for mycophenolic acid, normalized to a mycophenolate mofetil dose of 1 g, were AUC, 26.9 ± 13.2 μg ·hr/mL/g; C(max), 17.5 ± 5.4 μg/mL/g; t(max), 0.9 ± 0.6 hr; and C(min), 1.5 ± 1.1 μg/mL/g. The free fraction of mycophenolic acid was 1.8% ± 0.7%. AUC ratios of MPAG:mycophenolic acid and AcMPAG:mycophenolic acid were 13.0 ± 5.8 and 0.1 ± 0.2, respectively.


CONCLUSIONS
Overall exposure and C(min) values for tacrolimus were similar but C(max) values were higher than those documented in renal transplant patients treated with corticosteroid-based regimens. This may have clinical implications in corticosteroid-free patients experiencing symptoms of tacrolimus toxicity despite trough levels within target ranges. Mycophenolic acid exposure increased with time, but AUC values fell within the range expected for patients receiving concurrent corticosteroids.
Solid Organ Transplantation, Vancouver Coastal HealthAuthority, Vancouver, BC, Canada.
Erica D
ED
Greanya
Eric
E
Poulin
Nilufar
N
Partovi
R Jean
RJ
Shapiro
Mai
M
Al-Khatib
Mary H H
MH
Ensom
D000328:Adult; D019540:Area Under Curve; D003430:Cross-Sectional Studies; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use
D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid; D016559:Tacrolimus