Cystatin C and myeloperoxidase based mycophenolic acid dosage optimization in pediatric anti-neutrophilic cytoplasmic antibody-associated nephritis

Abstract

Aims Mycophenolic acid (MPA) is typically used for anti-neutrophilic cytoplasmic antibody associated nephritis (AAN) but with large individual variability of pharmacokinetics. This study aims to investigate clinical factors impacting MPA disposal so as to simulate dosage regimen in pediatric AAN. Methods We conducted a retrospective study in 25 children with AAN treated with MPA. A population pharmacokinetic model was developed to explore the effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimens. Results A total of 391 MPA concentrations from 25 patients were analyzed. MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL, Vc, Vp, and Q were 0.45 h-1, 9.86 L/h, 19.69 L, 408.32 L and 23.01 L/h, respectively. Dosage form significantly affected drug absorption. CL significantly decreased with increasing cystatin C, while with decreasing myeloperoxidase. Cystatin C was superior to serum creatinine in predicting CL of MPA. A dose of 650 mg/m2 was required to achieve the target exposure in children with normal renal function and no inflammation. Dose of MPA in patients with renal failure was almost 1/3 that of normal kidney function. The combined effects of myeloperoxidase and renal function resulted in a 6-fold range in MPA dose. Conclusions 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 children.