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Pharmacokinetics and limited sampling strategies of mycophenolic acid in islet transplant recipients Al-Khatib, Mai


Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) is an immunosuppressant that is used in organ transplantation and exhibits wide inter-patient variability in its pharmacokinetic properties in various transplant populations. However, only one study has addressed the pharmacokinetics of MPA in the islet transplant population. The objectives of our study were to characterize the pharmacokinetics of MPA and its two glucuronidated metabolites as well as develop limited sampling strategies (LSSs) for the estimation of MPA area-under- the curve (AUC) in the islet transplant population. Sixteen stable islet transplant recipients on steady-state MPA therapy were recruited. The patients were also on tacrolimus-based, steroid-free immunosuppressant regimens. Blood samples were collected at 0, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose. Concentrations of MPA, free MPA, 7-O-mycophenolic acid glucuronide (MPAG) and acyl-mycophenolic acid glucuronide (AcMPAG) in the plasma samples were measured by a high performance liquid chromatography-ultraviolet detection technique. Conventional pharmacokinetic parameters were determined by non-compartmental analysis. Multiple regression analysis was used to develop the LSSs, using all 16 patients’ profiles. The resulting equations were validated for their bias and precision using the jackknife method. There was large inter-patient variability in all pharmacokinetic parameters of MPA, MPAG and AcMPAG. Reasons for this variability are multifactorial and should be the focus of future multicenter studies. Four 3-concentration and one 2-concentration LSS met predetermined criteria and had conventional sampling times. The LSS that we recommend is the one utilizing two concentrations: AUC=1.547+1.417C1+9.448C4. This equation is convenient and can be useful for clinicians in optimizing patient care.

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