1051 We previously reported an unexpected augmentation of mycophenolic acid (MPA) levels in a group of patients receiving mycophenolate mofetil (MMF) in combination with tacrolimus (FK) versus a matched group of patients receiving the same dose of MMF in combination with cyclosporine (CsA). In order to confirm this observation using a bioequivalent study design, 13 stable renal transplant patients at least 6 months post-Tx who were receiving CsA and 2g/day (1g bid) MMF were converted to FK while maintaining the same MMF dose. A 12-hour pharmacokinetic (PK) analysis was performed for both MPA and its glucuronide derivative (MPAG) before and 3 weeks after conversion. After the second PK analysis was performed, the MMF dose was reduced to 1g/day (0.5g bid) while the patients continued to receive FK. The most significant change after the switch to FK was in the in MPA trough levels, which increased in 12/13 patients and doubled on average (2.7±1.3 ug/ml on CsA vs 5.2±2.5ug/ml on FK, p=0.0008, paired student t-test). There was also an increase in the MPA AUC0-12 from 62±17 ug-hr/ml before to 81±27 ug-hr/ml after the switch (p=0.007). The average calculated fluctuation about the mean MPA concentration was significantly lower in all patients tested as well as on average (425±170% vs 240±89%, p=.00005). The MPAG PK profiles compare much differently than those of MPA. One observation associated with the switch from CsA to FK was that 10/13 patients displayed a drop in CrCl. In three of the patients there was a >25% decrease in CrCl, resulting in an associated "backup" of MPAG in their plasma. When the remaining 10 patients were used for the MPAG PK analysis, all of the major PK parameters (Cmin, Cmax, and AUC0-12) were lower after the switch to FK, although only the Cmax (144±20 ug/hr vs 100±11 ug/ml, p=0.005) and AUC0-12 (1,200±200 ug-hr/m/hr 850±103 ug-hr/ml, p=0.006) were statistically significant. All patients displayed a decrease in the % of MMF excreted as MPAG in the urine, which was also significant on average (97±16% vs 76±11%, p=0.0002). For both MPA and MPAG, PK values with FK and a 1g/day MMF dose were approximately one-half of the FK and 2g/day MMF regimen. The majority of patients (12/13) experienced some side effects known to be associated with FK (neurotoxicity, nephrotoxicity) or MMF (gastrointestinal toxicity) after the switch from CsA to FK while receiving 2g/d MMF. All were easily resolved through minor modifications of the patients' medication (except for MMF, which was always maintained at a fixed dose). There were no significant adverse events after the patients' MMF dose was reduced to 1g/day. The data indicate that FK exerts an inhibitory effect on the conversion of MPA to MPAG in a bioequivalence study in long-term renal transplant recipients. There is also a possibility that FK may somehow affect the recirculation of MPAG, perhaps independent of its influence on MPA metabolism. Irregardless of the mechanism, we have now confirmed that special dosage consideration is warranted for renal transplant patients receiving FK in combination with MMF as opposed to CsA.
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Zucker et al. (1999) studied this question.