Abstract
Objective
To identify determinants of mycophenolic acid (MPA) pharmacokinetics (PK) in pediatric patients with lupus nephritis (LN), and to develop a limited sampling strategy (LSS) for estimating MPA-AUC0-12 h.Methods
A single-center observational study enrolled biopsy-proven LN receiving mycophenolate mofetil (MMF) at least 7 consecutive days. Univariate analysis were performed to assess associations between MPA PK parameters and demographics, genetic polymorphisms, clinical variables. LSS models for predicting MPA-AUC0-12 h were developed via multivariate stepwise regression analysis.Results
Statistically significant correlations were observed between MPA-AUC0-12 h and MMF dose, plasma albumin level, estimated glomerular filtration rate, and genetic polymorphisms in HNF1A (rs56097722) and CYP2C8 (rs1058932). CES2 (rs11075646) was significantly associated with MPA half-life (T₁/₂). Single timepoint MPA concentrations demonstrated poor predictive performance for AUC0-12 h(R2 = 0.194-0.553). The optimal LSS model was achieved with four timepoints: MPA-AUC0-12 h = 2.935 + 0.716·C0.5 + 1.305·C1.5 + 3.176·C4 + 4.705·C9 (R2 = 0.945). This model demonstrated good predictive performance (MPE = 1.84%, MAPE = 9.47%, RMSE = 12.53%). The LSS model was validated internally and externally for stability and applicability.Conclusion
Reduced MPA exposure was associated with MMF doses 1·day⁻1, hypoproteinemia, preserved or mildly impaired renal function, and HNF1A rs56097722 C/C or CYP2C8 rs1058932 G/G genotypes. CES2 rs11075646 C/C tended to correlate with a shorter MPA T₁/₂. The validated LSS models are recommended for estimating MPA-AUC0-12 h in pediatric LN, which are expected to simplify the therapeutic drug monitoring process.