Population pharmacokinetic and dose optimization of mycophenolic acid in children with anti-neutrophilic cytoplasmic antibody-associated nephritis

Purpose Anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis is a rare autoimmune disease. Mycophenolic acid (MPA) is widely used for ANCA-associated nephritis (AAN) but with large pharmacokinetic variability. This study aims to investigate clinical factors impacting MPA disposition in pediatric AAN. Methods We retrospectively collected 391 MPA concentrations from 25 children diagnosed with AAN. A population pharmacokinetic model was developed to explore the potential effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimen. Results MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for K-a, CL/F, V-c/F, V-p/F, and Q/F were 0.45 h(-1), 9.86 L/h, 19.69 L, 408.32 L, and 23.01 L/h. Dosage form significantly affected drug absorption. CL/F significantly decreased with increasing cystatin C, while decreasing with myeloperoxidase. Cystatin C was superior to serum creatinine in predicting apparent clearance of MPA. A dose regimen of 650 mg/m(2) twice daily was required to achieve target exposure in children with normal renal function and no inflammation. The combined effects of myeloperoxidase concentration and renal function resulted in a sixfold range of MPA dose. Conclusion This was the first study of MPA population pharmacokinetic model in children with AAN. Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN.