Abstract | 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.
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Authors | Dirk R J Kuypers, Kathleen Claes, Pieter Evenepoel, Bart Maes, Yves Vanrenterghem |
Journal | Clinical pharmacology and therapeutics
(Clin Pharmacol Ther)
Vol. 75
Issue 5
Pg. 434-47
(May 2004)
ISSN: 0009-9236 [Print] United States |
PMID | 15116056
(Publication Type: Journal Article)
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Chemical References |
- Cholesterol, HDL
- Cholesterol, LDL
- Serum Albumin
- Triglycerides
- Cholesterol
- Creatinine
- Mycophenolic Acid
- Tacrolimus
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Topics |
- Area Under Curve
- Cholesterol
(blood)
- Cholesterol, HDL
(blood)
- Cholesterol, LDL
(blood)
- Creatinine
(blood)
- Drug Therapy, Combination
- Female
- Germany
- Graft Rejection
- Humans
- Kidney Transplantation
- Male
- Middle Aged
- Mycophenolic Acid
(administration & dosage, adverse effects, pharmacokinetics)
- Postoperative Complications
- Prospective Studies
- Serum Albumin
- Tacrolimus
(administration & dosage, adverse effects, pharmacokinetics)
- Triglycerides
(blood)
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