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

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.

Duke Scholars

Author Daniel Gonzalez Medicine, Clinical Pharmacology