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.