Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen

• Published in: American journal of health-system pharmacy 2012-01, Vol.69 (2), p.134-142
• Main Authors: Greanya, Erica D., Poulin, Eric, Partovi, Nilufar, Shapiro, R. Jean, Al-Khatib, Mai, Ensom, Mary H. H.
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Area Under Curve; Comparative analysis; Cross-Sectional Studies; Female; Glucuronides - pharmacokinetics; Health aspects; Humans; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Kidney Transplantation - methods; Male; Middle Aged; Models, Biological; Mycophenolate mofetil; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacokinetics; Mycophenolic Acid - therapeutic use; Organ transplant recipients; Pharmacokinetics; Prospective Studies; Tacrolimus; Tacrolimus - pharmacokinetics; Tacrolimus - therapeutic use
• ISSN: 1079-2082; 1535-2900
• DOI: 10.2146/ajhp110287

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