Clinical pharmacokinetics · 2025
Exploring the Influence of Obesity and CYP2 C19 Genotype on Lansoprazole Pharmacokinetics in Pediatric Patients: A Population Modeling Approach.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Helfer Victória E, Gonzalez Daniel, Kyler Kathryn E, Dunlap Tyler C, Williams Veronica, Radford Jansynn, Selvarangan Rangaraj, Sasidharan Anjana, Chan Sherwin, Artz Nathan, Retke Brandon, Toren Paul, Gibson Kim, Shakhnovich Valentina
Аннотация
BACKGROUND AND OBJECTIVE: Pediatric pharmacokinetics pose unique challenges, particularly concerning drug dosing in the presence of obesity and genetic variability in drug-metabolizing enzymes such as cytochrome P450 (CYP) 2C19. This study aimed to develop a lansoprazole pediatric population pharmacokinetic (popPK) model considering obesity, obesity-associated changes in inflammatory cytokines and the liver, and CYP2C19 genotype, and to assess implications for dosing strategies.
METHODS: Pediatric subjects with and without obesity (6-21 years, n = 47) received one oral dose of 1.2 mg/kg fat-free mass (FFM), not exceeding 60 mg. Plasma concentrations were measured at multiple time points, and a popPK analysis using NONMEM with stepwise covariate modeling was performed. Simulations compared exposures between children without and with obesity (BMI percentile ≥ 95th) after two dosing strategies: U.S. Food and Drug Administration (FDA)-approved total body weight-tiered and FFM-based dosing.
RESULTS: A total of 537 lansoprazole concentrations were modeled using a two-compartment model with Weibull absorption and linear elimination. Parameters were allometrically scaled to FFM with fixed exponents of 0.75 for clearances and 1 for volumes. CYP2C19 was identified as a significant covariate for CL/F. No significant differences in lansoprazole exposure were observed between children with and without obesity, with both dosing approaches. Higher exposure was noted in poor/intermediate metabolizers of CYP2C19. FFM-based dosing led to similar levels of exposure between children (aged 6-11 years) and adolescents (aged 12-17 years).
CONCLUSIONS: Obesity was not associated with differences in lansoprazole pharmacokinetics in children. A FFM-based dosing approach could result in comparable exposure between children and adolescents. Dose adjustments are supported for poor/intermediate metabolizers of CYP2C19.
METHODS: Pediatric subjects with and without obesity (6-21 years, n = 47) received one oral dose of 1.2 mg/kg fat-free mass (FFM), not exceeding 60 mg. Plasma concentrations were measured at multiple time points, and a popPK analysis using NONMEM with stepwise covariate modeling was performed. Simulations compared exposures between children without and with obesity (BMI percentile ≥ 95th) after two dosing strategies: U.S. Food and Drug Administration (FDA)-approved total body weight-tiered and FFM-based dosing.
RESULTS: A total of 537 lansoprazole concentrations were modeled using a two-compartment model with Weibull absorption and linear elimination. Parameters were allometrically scaled to FFM with fixed exponents of 0.75 for clearances and 1 for volumes. CYP2C19 was identified as a significant covariate for CL/F. No significant differences in lansoprazole exposure were observed between children with and without obesity, with both dosing approaches. Higher exposure was noted in poor/intermediate metabolizers of CYP2C19. FFM-based dosing led to similar levels of exposure between children (aged 6-11 years) and adolescents (aged 12-17 years).
CONCLUSIONS: Obesity was not associated with differences in lansoprazole pharmacokinetics in children. A FFM-based dosing approach could result in comparable exposure between children and adolescents. Dose adjustments are supported for poor/intermediate metabolizers of CYP2C19.