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Background and Objective <p>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 <i>CYP2C19</i> genotype, and to assess implications for dosing strategies. </p> Methods <p>Pediatric subjects with and without obesity (6–21 years, <i>n</i> = 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. </p> Results <p>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. <i>CYP2C19</i> 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 <i>CYP2C19</i>. FFM-based dosing led to similar levels of exposure between children (aged 6–11 years) and adolescents (aged 12–17 years).</p> Conclusions <p>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.</p>

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Exploring the Influence of Obesity and CYP2 C19 Genotype on Lansoprazole Pharmacokinetics in Pediatric Patients: A Population Modeling Approach

  • 期刊论文

  • 发表日期：

    2025年5月16日

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  • Victória E. Helfer,
  • Daniel Gonzalez,
  • Kathryn E. Kyler,
  • Tyler C. Dunlap,
  • Veronica Williams,
  • Jansynn Radford,
  • Rangaraj Selvarangan,
  • Anjana Sasidharan,
  • Sherwin Chan,
  • Nathan Artz,
  • Brandon Retke,
  • Paul Toren,
  • Kim Gibson,
  • Valentina Shakhnovich

摘要

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.