Population Pharmacokinetic Study of Tacrolimus in Pediatric Patients with Primary Nephrotic Syndrome: A Comparison of Linear and Nonlinear Michaelis Menten Pharmacokinetic Model

TL;DR

This study compares linear and nonlinear pharmacokinetic models for tacrolimus in children with primary nephrotic syndrome, finding the nonlinear Michaelis Menten model more accurate for guiding dosing adjustments.

Contribution

It introduces a nonlinear Michaelis Menten pharmacokinetic model for tacrolimus in pediatric PNS, outperforming traditional linear models in predictive accuracy.

Findings

Nonlinear model better predicts tacrolimus PK in children.

Body weight, co-therapy drugs, and CYP3A5*3 genotype are key factors.

Proposed dosing regimens based on nonlinear PK model.

Abstract

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.