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For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients.

Mycophenolate mofetil (MMF) is increasingly used for the treatment of autoimmune diseases (AID). In renal transplant recipients, it has been demonstrated that adjustment of the MMF dose according to the area under the plasma concentration versus time curve (AUC) of mycophenolic acid (MPA), the active moiety of MMF, improves clinical outcome. The aim of this study was to develop a maximum a posteriori Bayesian estimator (MAP-BE) to estimate MPA AUC(0-12) in patients with AID using a limited number of samples. The predictive performance of the MAP-BE was compared with a multiple linear regression method. Full MPA concentration versus time curves were available from 38 patients with AID treated with MMF. Nonlinear mixed-effect modeling was used to develop a population pharmacokinetic model. Patients were divided in an index and a validation data set. The pharmacokinetic model derived from the index data set was used to develop several MAP-BEs. The Bayesian estimators were used to predict AUC(0-12) in the validation data set on the basis of a limited number of blood samples. The bias and precision of these predictions were compared with those of limited sampling strategies developed with multiple linear regression. The absorption of MPA was described with 2 first-order processes with a short and a long lag time and a subsequent first-order elimination. The 2-compartment model accounted for the enterohepatic recirculation of MPA as well. Using 1-4 samples, MPA AUC(0-12) was adequately estimated by the MAP-BE. Bias (-5.5%) was not significantly different from zero, and precision was below 27%. The predictive performance of the multiple linear regression method was comparable. In conclusion, MAP-BEs were developed for the estimation of MPA AUC(0-12) in patients with AID. The predictive performance was good and comparable to those of the multiple linear regression method. Due to its flexibility with respect to sample times, the MAP-BE may be preferred over the multiple linear regression method.