Pk/Pd Study Of Mycophenolate Mofetil In Children With Systemic Lupus Erythematosus To Inform Model-Based Precision Dosing

Objectives: To evaluate the mycophenolic acid [MPA, the active form of mycophenolate mofetil (MMF)] pharmacokinetic parameters in relation to clinical response to identify target exposure ranges in pediatric patients with systemic lupus erythematosus (SLE).Methods: This was a retrospective study using pharmacokinetic data collected in 67 pediatric patients aged 4-18 years with SLE. Target MPA exposures for effective inhibition of SLE activity (as measured by SLE disease Activity Index (SLEDAI), active SLE was defined as a SLEDAI score of >= 6, and a controlled disease was defined as a SLEDAI score of <= 4) were assessed by receiver operating characteristic (ROC) curve and logistic regression. Exposure-response models were developed to quantitatively describe the relationship between SLEDAI score and AUC(0-12) or C-trough, respectively.Results: The MPA AUC(0-12) in patients with active SLE was significantly lower than that in patients with inactive SLE. ROC analysis revealed that an AUC(0-12) threshold of 39 mu g h/ml or a C-trough of 1.01 mu g/ml was associated with the lowest risk of active SLE. Logistic regression analysis revealed that an AUC(0-12) of less than 34 mu g h/ml or a C-trough of less than 1.2 mu g/ml probably is associated with active SLE. The results of the exposure-response modeling also indicated that an AUC(0-12) less than 32 mu g h/ml or a C-trough less than 1.1 mu g/ml was associated with suboptimal clinical outcome. An AUC(0-12) above 50 mu g h/ml or a C-trough above 1.7 ug/ml was associated with disease control.Conclusion: Both AUC(0-12) and C-trough of MPA are predictive of the likelihood of active SLE in pediatric patients receiving MMF. An individualized dosing regimen of MMF, with a target AUC(0-12) or C-trough, should be considered for SLE patients.