Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation.

University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Transplantation reviews (Orlando, Fla.) (Impact Factor: 2.68). 03/2011; 25(2):78-89. DOI: 10.1016/j.trre.2011.01.001
Source: PubMed

ABSTRACT Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppressive therapy in pediatric renal and heart transplant recipients. Children undergo developmental changes (ontogeny) of drug disposition, which may affect drug metabolism of the active compound mycophenolic acid (MPA). Therefore, a detailed characterization of MPA pharmacokinetics and pharmacodynamics in this patient population is required. In general, the overall efficacy and tolerability of MMF in pediatric patients appear to be comparable with those in adults, except for a higher prevalence of gastrointestinal adverse effects in children younger than 6 years. The currently recommended dose in pediatric patients with concomitant cyclosporine is 1200 mg/m(2) per day in 2 divided doses; the recommended MMF dose with concomitant tacrolimus or without a concurrent calcineurin inhibitor is 900 mg/m(2) per day in 2 divided doses. Recent data suggest that fixed MMF dosing results in MPA underexposure (MPA-area under the concentration-time curve (AUC(0-12)), <30 mg × h/L) early posttransplant in approximately 60% of patients. To achieve adequate MPA exposure in most patients, an initial MMF dose of 1800 mg/m(2) per day with concomitant cyclosporine and 1200 mg/m(2) per day with concomitant tacrolimus for the first 2 to 4 weeks posttransplant has been suggested. As in adults, there is an approximately 10-fold variability in dose-normalized MPA-AUC(0-12) values between pediatric patients after renal transplantation, strengthening the argument for concentration-controlled dosing of the drug. Although the clinical utility of therapeutic drug monitoring of MPA for graft outcome and patient survival is still controversial, potential indications are the avoidance of underimmunosuppression, particularly in patients with high immunologic risk in the initial period posttransplant, in patients who are treated with protocols that explore the possibilities of calcineurin inhibitor minimization, withdrawal or even complete avoidance, and steroid withdrawal or avoidance regimens that might also benefit from intensified therapeutic drug monitoring of MPA. An additional indication especially in adolescent patients is the monitoring of drug adherence. Therapeutic drug monitoring of MPA in pediatric solid organ transplantation using limited sampling strategies is preferable over drug dosing based on trough level monitoring only. Several validated pediatric limited sampling strategies are available. Clearly, more research is required to determine whether pediatric patients will benefit from therapeutic drug monitoring of MPA for long-term maintenance immunosuppression with MMF.

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    ABSTRACT: Mycophenolate mofetil (MMF) is an effective immunosuppressive agent that has been frequently used in laboratory animals including swine; however, the pharmacokinetic properties of MMF in swine have not been studied. This short-term study was designed to evaluate the feasibility and the pharmacokinetic profiles of MMF therapy in neonatal swine. Twelve neonatal pigs were randomized into four groups including one control and three treated groups with oral MMF administered at 0.5, 1, and 2 g/m(2)/d for 4 days, divided by 2 half-doses at 9:00 and 17:00 (except day 4 during which MMF was not administered at 17:00). Blood samples were collected at 9:00 on days 0, 2, 3 and 4 for complete blood count and hepatic/renal function examination; the trough concentration of plasma mycophenolic acid (MPA) was also determined. On days 2 and 4, blood was collected to determine the area under the curve (AUC) of plasma MPA concentration. Animal body-weight growth and manifestations of MMF side-effects such as anorexia, vomiting, and diarrhea were also observed. MMF has no acute hepatic/renal toxicity in newborn pigs; however, less body-weight growth was observed in treated groups. In the control group, a spontaneous increase of lymphocyte count was observed; in contrast, MMF therapy with doses of 1 and 2 g/m(2)/d reduced both lymphocyte and monocyte counts of piglets. Oral MMF had high bioavailability in neonatal swine. MPA-AUC0-12h of doses 0.5, 1, and 2 g/m(2)/d was 22.00 ± 3.32, 57.57 ± 34.30, and 140.00 ± 19.70 μg × h/mL, respectively. Neither MPA trough concentration (MPA-C0), nor MPA maximum concentration (MPA-Cmax) or MPA-AUC0-6h had high correlation with MMF-dose. For surveillance of MPA exposure, MPA-C0 had significant correlation with MPA-AUC0-12h (Spearman's ρ = 0.933, AUC0-12h = 17.882 × C0 + 14.479, r(2) = 0.966). To reach adequate drug exposure and to reduce dose-dependent side effects, an MMF dose of 1 g/m(2)/d is recommended to be used as an initial dose for immunosuppressive therapy in piglets, and MPA-C0 monitoring is the most practical strategy for experimental transplantation study. Copyright © 2014 Elsevier Inc. All rights reserved.
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