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.