  Background Little is known about the population pharmacokinetics (PPK) of
tacrolimus (TAC) in pediatric primary nephrotic syndrome (PNS). This study
aimed to compare the predictive performance between nonlinear and linear PK
models and investigate the significant factors of TAC PK characteristics in
pediatric PNS. Methods Data were obtained from 71 pediatric patients with PNS,
along with 525 TAC trough concentrations at steady state. The demographic,
medical, and treatment details were collected. Genetic polymorphisms were
analyzed. The PPK models were developed using nonlinear mixed effects model
software. Two modeling strategies, linear compartmental and nonlinear Michaelis
Menten (MM) models, were evaluated and compared. Results Body weight, age,
daily dose of TAC, co-therapy drugs (including azole antifungal agents and
diltiazem), and CYP3A5*3 genotype were important factors in the final linear
model (onecompartment model), whereas only body weight, codrugs, and CYP3A5*3
genotype were the important factors in the nonlinear MM model. Apparent
clearance and volume of distribution in the final linear model were 7.13 L/h
and 142 L, respectively. The maximal dose rate (Vmax) of the nonlinear MM model
was 1.92 mg/day and the average concentration at steady state at half-Vmax (Km)
was 1.98 ng/mL. The nonlinear model described the data better than the linear
model. Dosing regimens were proposed based on the nonlinear PK model.Conclusion
Our findings demonstrate that the nonlinear MM model showed better predictive
performance than the linear compartmental model, providing reliable support for
optimizing TAC dosing and adjustment in children with PNS.
