Steady-state mycophenolate mofetil pharmacokinetic parameters enable prediction of systemic lupus erythematosus clinical flares: an observational cohort study

Abstract

IntroductionThe aim of this study was to determine whether mycophenolate mofetil (MMF) pharmacokinetics (PK) under combined MMF and prednisone remission-maintenance therapy can predict systemic lupus erythematosus (SLE) clinical flares.MethodsAt inclusion, steady-state PK parameters of the MMF active form, mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) were determined for 25 stable SLE patients without renal manifestations. Disease activity was assessed during 6 months of follow-up. Potential relationships between those entry MMF-PK variables and clinical outcome were analyzed.ResultsMMF controlled disease activity in 17 patients (successes) and failed to do so for 8 others (failures). For failures and successes, respectively, entry MPA areas under the time-concentration curve between 0 and 12 hours (AUC0-12 h) (medians: 37.7 vs 73.1 mg/h/L, P = 0.003) and MPA 12-hour trough concentrations (C12 h) (medians: 1.5 vs 3.7 mg/L, P = 0.008) were significantly lower, and inclusion MPAG/MPA C12 h ratios (medians: 18.7 vs 10.2, P = 0.02) were significantly higher. According to our receiver operating characteristics curve analysis, MPA C12 h was best able to discriminate a flare during follow-up (93% sensitivity, 85% specificity). A 3-mg/L cut-off had 92% negative-predictive value for developing a flare during follow-up.ConclusionsFor our SLE patients without renal manifestations, clinical flares developing under maintenance therapy were associated with steady-state inclusion MPA C12 h < 3 mg/L.

Therapeutic Drug Monitoring of Mycophenolic Acid in Lupus Nephritis

“…Moreover, the association was made that the higher MPA C 12 h levels provide better protection from recurrence of active disease. This was proved in the other study conducted by Djabarouti et al, 26 in which the measurement of MPA C 12 h enabled prediction of clinical outcomes of patients suffering from SLE without renal manifestations. Therefore, target threshold of 3 mg/L is now recommended by the authors.…”

Lower 12-hour Trough Concentrations of Mycophenolic Acid in Patients with Active Systemic Vasculitides Taking Mycophenolate Mofetil

“…However, no recommendations concerning optimal dose of MMF for AAV are available, and a high relapse rate might compromise its use as a first-line remission-maintenance therapy 3 . An association between SLE activity and the pharmacokinetics of MPA has been described 4,5,6 . We previously reported that, for patients with SLE without renal manifestations, clinical flares under MMF were associated with 12-h trough concentrations (C 12h ) of MPA that were < 3 mg/l 5 .…”

“…In our study, active disease was associated with a significantly lower MPA C 12h , suggesting that therapeutic drug monitoring in vasculitis patients with dose adaptation would probably improve their outcomes over a fixed-dose strategy. Such monitoring was previously recommended for patients with SLE, whose routine MPA C 12h measurements could predict their clinical outcomes 4,5 .…”

Therapeutic drug monitoring of mycophenolate mofetil for the treatment of severely active lupus nephritis

“…6,7 Subsequent studies involving pharmacokinetics of MMF in patients with autoimmune disease have highlighted the interindividual variability of MPA levels. [8][9][10][11][12] MPA exposure also correlated with disease activity of SLE and immunologic parameters such as complement component 3 (C3). [9][10][11][12][13] According to our previous study, the area under the curve of MPA from 0-12 hours (MPA-AUC 0-12h ) >45 mg.h/L was associated with good therapeutic response in patients with active LN.…”

“…[8][9][10][11][12] MPA exposure also correlated with disease activity of SLE and immunologic parameters such as complement component 3 (C3). [9][10][11][12][13] According to our previous study, the area under the curve of MPA from 0-12 hours (MPA-AUC 0-12h ) >45 mg.h/L was associated with good therapeutic response in patients with active LN. 11 MPA plasma concentration at 1 hour after taking MMF (MPA-C1) was found to be the best predictor of MPA-AUC 0-12h 11 with the MPA-C1 of >13 mg/L highly correlated with the targeted MPA-AUC 0-12h of >45 mg.h/L.…”