Free mycophenolic acid exposure for therapeutic drug monitoring in paediatric lupus nephritis: associations with treatment response and haematologic toxicity
Xuerui Tong, Jingxuan Lin, Lizhi Chen, Yutong Guo, Baojing Liu, Min Huang, Kejing Tang, Pan Chen, Xiaoyun JiangObjective
This study aimed to evaluate the associations of free mycophenolic acid (f-MPA) concentration and total MPA (t-MPA) concentration with treatment response and haematologic toxicity and to determine whether f-MPA provides additional safety-related value for therapeutic drug monitoring (TDM) in patients with paediatric lupus nephritis (LN) treated with mycophenolate mofetil (MMF).
Methods
Sixty-five patients with paediatric LN receiving MMF were prospectively enrolled. The t-MPA and f-MPA were measured simultaneously using validated ultrafiltration and LC-MS/MS. Full pharmacokinetic profiles were obtained over 12 hours, and area under the concentration-time curve (AUC) was calculated for t-MPA (t-MPA-AUC) and f-MPA (f-MPA-AUC). Univariate analysis identified factors influencing efficacy (relapse-free survival) and adverse drug reaction (ADR) over 12 months. Receiver operating characteristic (ROC) curves established predictive thresholds and Kaplan-Meier methods analysed time-to-event.
Results
The 12-month relapse-free rate was 78.7% (95% CI 66.6% to 90.9%). Both t-MPA-AUC and f-MPA-AUC significantly correlated with relapse-free survival (ROC AUC 0.70 each; optimal thresholds: t-MPA-AUC=31.63 µg·h/mL, f-MPA-AUC=354.45 ng·h/mL). The average remission duration above these thresholds was 10.88 and 11.00 months. The overall MMF-related ADR incidence was 25.2%, including 17 haematological events (26.2%). The t-MPA-AUC, f-MPA-AUC, glucose, β2-microglobulin and C3 were haematological ADR risk factors. The f-MPA-AUC independently predicted haematological ADRs (optimal threshold: 492.96 ng·h/mL; specificity 86.2%).
Conclusion
Both t-MPA-AUC and f-MPA-AUC effectively predict MMF efficacy in paediatric LN. However, f-MPA-AUC demonstrates superior predictive value for safety outcomes, specifically haematological ADRs. This supports f-MPA as a potentially better TDM metric for optimising MMF therapy safety in this population.