Article Figures & Data
Figures
- Figure 1.
Pharmacokinetic behavior of mycophenolate mofetil (MMF) after oral administration (see text for details). MMF is converted to mycophenolic acid (MPA) presystemically, and then is subsequently metabolized to its glucuronide (Glu) conjugates, MPAG and AcMPAG, by different isoforms of UDP glucuronidyl transferses (UGT) in the liver. Pathways of enterohepatic circulation of MPA via the glucuronide conjugate metabolites are shown.
Tables
- Table 1.
Correlation between MMF pharmacokinetics and clinical outcomes in renal transplantationa
Study No. of Patients Follow-Up Time Calcineurin Inhibitors TDM MPA Parameters Assay Method Clinical Outcomes Borrows et al. (55) 121 1 yr Tacrolimus Fixed dosage C0 EMIT >1.60 mg/L is associated with low rejection rates; >2.75 mg/L is associated with hematologic toxicity and diarrhea Cattaneo et al. (48) 46 9 mo CsA Fixed dosage AUC0-12 h, C0 HPLC AUC >40 mg·h/L or C0 >1.5 mg/L is associated with better renal functions; there was a negative correlation between free MPA levels with hematocrit levels Hale et al. (36) 156 6 mo CsA Dosage adjustment by Bayesian estimation AUC0-12 h HPLC AUC of 15 and 25 mg·h/L showed 50 and 75% maximal achievable efficacy, respectively Kiberd et al. (50) 94 3 mo CsA Fixed dosage AUC0-12 h, C0 HPLC AUC of 22 mg·h/L was a threshold for prediction of acute rejection episodes Kuypers et al. (20) 22 1 yr Tacrolimus Fixed dosage C0 HPLC C0 of MPA (total or free) and its metabolites did not correlate with clinical efficacy or toxicity Mourad et al. (46) 51 —b Tacrolimus Fixed dosage AUC0-12 h, C0 EMIT AUC of 38 mg·h/L was a threshold for toxicity (sensitivity 83%; specificity 60%) Oellerich et al. (35) —b 6 mo CsA Fixed dosage AUC0-12 h, C0 HPLC AUC of approximately 30 to 60 mg·h/L seems to be a reasonable target for early posttransplantation period Pawinski et al. (33) 33 3 mo CsA or tacrolimus Fixed dosage AUC0-12 h, C0 HPLC AUC of 27.5 mg·h/L and C0 of 1.1 mg/L were threshold values for prediction of acute rejection episodes Pillans et al. (39) 27 1 mo CsA Fixed dosage AUC0-12 h, C0 HPLC AUC <30 mg·h/L was associated with increased incidence of rejection; no association was found between the incidence of acute rejection and C0 van Gelder et al. (44) 154 6 mo CsA Dosage adjustment by Bayesian estimation AUC0-12 h, C0 —b Incidence of acute rejection in low, intermediate, and high MPA concentration groups (16, 32, and 60 mg·h/L, respectively) were 28, 15, and 12%, respectively Weber et al. (34) 54 6 mo CsA Fixed dosage AUC0-12 h, C0 HPLC AUC of 33.8 mg·h/L differentiates acute rejection (sensitivity 75%; specificity 64%) Initial dosing CsA-based regimen: start MMF at 1.5 g twice daily, and then adjust dosage on the basis of TDM Tacrolimus-based regimen: start MMF at 1 g twice daily Frequency of monitoring and dose adjustment Days 3 and 7 and once during days 10 to 14 after transplantation Week 3 or 4 (optional) Occasions of substantial changes in immunosuppressant regimen Occasions that require evaluation of clinical events, such as drug-related toxicity or rejection Assay considerations Either HPLC or EMIT is acceptable for monitoring MPA target concentrations using EMIT are higher (as a result of cross-reactivity with AcMPAG) Target concentrations (HPLC) MPA AUC 30 to 60 mg·h/L in the first 30 d after transplantation MPA C0 CsA-based regimen: ≥1.3 mg/L tacrolimus-based regimen: ≥1.9 mg/L Special populations calcineurin inhibitor-sparing regimen a higher end of MPA target concentrations range is required altered protein binding: free drug MPA concentration can be higherb renal impairment high bilirubin Dosage adjustmentc 
↵a Data are summary of reference (45). AcMPAG, MPA-acyl-glucuronide.
↵b Because of extensive protein binding of MPA, free drug MPA concentration can be higher, although the total MPA concentration is within the target range. Therefore, under circumstances of altered protein binding, total MPA levels are difficult to assess.
↵c This recommendation is under assumption of dosage linearity in MPA pharmacokinetics, which may not exist in all cases.
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