J. T. Brown,1 S. M. Abdel-Rahman,2 L. Van Haandel,2 A. Gaedigk,2 J. S. Leeder2; 1University of Minnesota College of Pharmacy, Duluth, MN, 2Children's Mercy Kansas City, Kansas City, MO
BACKGROUND: The objective of this study was to determine the magnitude of effect of CYP2D6 genotype on atomoxetine (ATX) systemic exposure in children with ADHD.
METHODS: A single 0.43±0.07 mg/kg dose of ATX was administered to 23 children aged 6-17 years of age with CYP2D6 activity scores of 0 (n=4; PM), 0.5 (n=3; IM), 1 (n=8; EM1) and 2 (n=8; EM2) after an overnight fast. Plasma was obtained at 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours after dosing; two additional samples at 48 and 72 hr were obtained in PMs. ATX was measured by LC/MS/MS. Area under the curve (AUC) was calculated using the mixed log linear method and extrapolated to infinity AUC. ANOVA and Tukey's HSD were used for statistical comparisons.
RESULTS: CYP2D6 alleles found in the study patients were *1, *2, *2x2, *3, *4, *5, *9, *10, *17, and *29. Dose (mg/kg)-corrected AUC varied 25.8-fold across the study cohort, and was 2.5-fold higher in PMs (60.0±10.9 µM*h) compared to IMs (24.0±8.8 µM*h; p<0.0001), and 8.5- to 10.8-fold greater than the EM1 (7.1±17 µM*h; p<0.001) and EM2 groups (5.6±2.3 µM*h; p<0.0001), respectively (Figure).
CONCLUSION: Weight-based dosing of ATX is associated with a 25-fold range of systemic exposure in a treated population. CYP2D6 genotype-based dosing strategies should reduce variability in the dose-exposure relationship between individual patients.