Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients.

INTRODUCTION: Tacrolimus and mycophenolate mofetil are effective drugs characterized by specific toxicity profiles that may compromise their long-term use in renal transplant recipients. Clinicians, therefore, need reliable drug monitoring tools for relating efficacy and toxicity to drug exposure. Study design We conducted a prospective 12-month pharmacokinetic study of tacrolimus and mycophenolic acid in 100 de novo recipients. The aim was to examine whether tacrolimus and mycophenolic acid exposure parameters (predose trough blood concentration [C(0)], area under the concentration curve from 0 to 12 hours [AUC(0-12)], maximum blood or plasma concentration [C(max)], and dose) would reflect clinical efficacy and toxicity at different time points after transplantation (7 days, 6 weeks, and 3, 6, and 12 months).
RESULTS: Initially, after grafting, the tacrolimus AUC(0-12) was higher in recipients with infection (P =.01 on day 7, P =.02 at week 6), whereas the mycophenolic acid AUC(0-12) was not different. There was no difference in tacrolimus exposure between patients who had arterial hypertension or hyperlipidemia and those who did not. Patients with tacrolimus nephrotoxicity received a higher drug dose (P =.03) and had higher drug clearance (P =.02). From 3 months, recipients with anemia or leukopenia had higher mycophenolic acid AUC(0-12) (anemia, P =.03 at month 3 and P =.01 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year) and C(0) (anemia, P =.001 at month 3 and P =.001 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year). Finally, for recipients who did not simultaneously have a target tacrolimus AUC(0-12) of 150 ng x h/mL and a mycophenolic acid AUC(0-12) of 45 mg x h/L by day 7, the incidence of acute rejection tended to be higher (26.3%) compared with patients who reached both target values (7.7%) (P =.07).
CONCLUSIONS: Pharmacokinetic exposure parameters of tacrolimus and mycophenolic acid are related to specific drug-induced side effects in a time-dependent fashion. In addition, this study has provided a conceptual basis for defining a combined target therapeutic window for tacrolimus and mycophenolic acid based on sparse AUC(0-12) measurements.