BMC pharmacology & toxicology · 2026
Population pharmacokinetics of tacrolimus and CYP3A5-driven variability: implications for model-informed dose individualization in pediatric renal transplant recipients.
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Xajil-Ramos Lesly Yanira, Gándara-Mireles Jesús Alonso, Guerra-García Mariela, Rosales Rodrigo José Vargas, Toledo Andrea Mariela Ruano, Ocaña-Garrido Dulce Sofia, Lares-Asseff Ismael, Cóbar Oscar, Soveranis Sindy Méndez, Patrón-Romero Leslie, Almanza-Reyes Horacio, Lou-Meda Randall
Аннотация
BACKGROUND: Population pharmacokinetics and pharmacogenomics are essential tools for understanding interindividual variability in tacrolimus exposure in pediatric transplant recipients. Identifying clinical and genetic factors associated with tacrolimus disposition may support individualized dosing strategies. This study aimed to develop a population pharmacokinetic (PopPK) model of tacrolimus in pediatric renal transplant patients and evaluate the impact of CYP3A5 genotype and relevant clinical covariates on pharmacokinetic parameters.
METHODS: A total of 165 tacrolimus whole-blood concentrations from 51 pediatric patients receiving immunosuppressive therapy were analyzed at ≥ 6 months following renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling implemented in Monolix®, assessing associations between pharmacokinetic parameters and clinical, biochemical, and genetic covariates to explain interindividual variability.
RESULTS: A two-compartment model with first-order absorption adequately described tacrolimus pharmacokinetics in the study population. Estimated population parameters were: Ka = 2.1282 h⁻¹, CL = 0.01633 L/h/1.44 m², V1 = 0.09417 L/1.44 m², V2 = 0.9558 L/1.44 m², and Q = 0.0514 L/h/1.44 m². CYP3A5 genotype was significantly associated with clearance, and estimated glomerular filtration rate (eGFR) influenced both clearance and central volume of distribution. Age was positively associated with the absorption rate constant.
CONCLUSIONS: The developed PopPK model provided and adequate characterization of tacrolimus pharmacokinetics in pediatric renal transplant recipients. CYP3A5 genotype, eGFR, and age were identified as relevant covariates associated with interindividual pharmacokinetic variability. These findings provide a basis for future evaluation of model-informed individualized dosing strategies in this population.
METHODS: A total of 165 tacrolimus whole-blood concentrations from 51 pediatric patients receiving immunosuppressive therapy were analyzed at ≥ 6 months following renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling implemented in Monolix®, assessing associations between pharmacokinetic parameters and clinical, biochemical, and genetic covariates to explain interindividual variability.
RESULTS: A two-compartment model with first-order absorption adequately described tacrolimus pharmacokinetics in the study population. Estimated population parameters were: Ka = 2.1282 h⁻¹, CL = 0.01633 L/h/1.44 m², V1 = 0.09417 L/1.44 m², V2 = 0.9558 L/1.44 m², and Q = 0.0514 L/h/1.44 m². CYP3A5 genotype was significantly associated with clearance, and estimated glomerular filtration rate (eGFR) influenced both clearance and central volume of distribution. Age was positively associated with the absorption rate constant.
CONCLUSIONS: The developed PopPK model provided and adequate characterization of tacrolimus pharmacokinetics in pediatric renal transplant recipients. CYP3A5 genotype, eGFR, and age were identified as relevant covariates associated with interindividual pharmacokinetic variability. These findings provide a basis for future evaluation of model-informed individualized dosing strategies in this population.