Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine, 4-OH; N-desmethylatomoxetine, NDA; and 2- carboxymethylatomoxetine, 2-COOH) exposure following oral ATX dosing in ADHD children to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from ADHD children (n=23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic (PK) modeling approach was employed in which a model for ATX, 4-OH and NDA in plasma and urine, and 2-COOH in urine was developed. Plasma ATX, 4-OH and NDA were modeled using two-compartment models with first-order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4-OH, and systemic exposure of NDA. CL/F of ATX varied almost 7-fold across the CYP2D6 AS groups: AS 2: 20.02 L/h; AS 1: 19.00 L/h; AS 0.5: 7.47 L/h; and AS 0: 3.10 L/h. The developed model closely captures observed ATX, 4-OH and NDA plasma and urine, and 2-COOH urine profiles. Application of the model shows the potential for AS-based dosing recommendations for improved individualized dosing.PMID:38117180 | DOI:10.1002/cpt.3155
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research