Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD

Abstract

The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6-17 years of age diagnosed with attention-deficit hyperactivity disorder (ADHD) were stratified by CYP2D6 genotype into groups with 0 (poor metabolizers [PMs], n = 4), 0.5 (intermediate metabolizers [IMs], n = 3), one (extensive metabolizer [EM]1, n = 8) or two (EM2, n = 8) functional alleles and administered a single 0.5 mg/kg oral dose of atomoxetine (ATX). Plasma and urine samples were collected for 24 (IM, EM1, and EM2) or 72 hours (PMs). Dose-corrected ATX systemic exposure (area under the curve [AUC]0-∞ ) varied 29.6-fold across the study cohort, ranging from 4.4 ± 2.7 μM*h in EM2s to 5.8 ± 1.7 μM*h, 16.3 ± 2.9 μM*h, and 50.2 ± 7.3 μM*h in EM1s, IMs, and PMs, respectively (P < 0.0001). Simulated steady state profiles at the maximum US Food and Drug Administration (FDA)-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication.

Figure 1

Effect of CYP2D6 genotype on mean ± SD plasma concentration time profiles for ATX (panel A), 4-OH-ATX (panel B), and its N-desmethyl metabolite NDA (panel C). In panel B, lines of best fit are provided for total 4-OH-ATX (non-conjugated plus glucuronide conjugate), whereas the concentration-time profiles for the therapeutically active, non-conjugated form are presented within the shaded area. Concentrations of non-conjugated 4-OH-ATX are considerably lower than ATX concentrations at all time points, and do not contribute to any appreciable extent to total therapeutically active drug in any genotype group.

Figure 2

Association between CYP2D6 genotype expressed as activity score and total ATX systemic exposure (AUC_0-∞). As a single capsule of the available dosage forms was administered to provide a dose at or near the recommended starting dose of 0.5 mg/kg, the actual dose administered ranged from 0.34–0.59 mg/kg, and AUC_0-∞ data were normalized to a 0.5 mg/kg dose. The one participant with a CYP2D6 activity score of 3 (three functional alleles) included in the EM2 group is designated by the black symbol.

Figure 3

Urinary recovery of ATX and metabolites. The percentage of the administered dose recovered in 24 h (IM, EM1, EM2) or 72 h (PM) urine collections as ATX (panel A), NDA (panel B) and carboxy metabolites, products of subsequent biotransformation of initial 2-methylhydroxylation (panel C), is presented as a function of the percentage of the administered dose recovered as 4-OH-ATX. Recovery exceeded 100% of the dose in two subjects (~105%). 4-OH-ATX was the most abundant single metabolite recovered in all CYP2D6 genotype groups, but the hydroxycarboxy products of initial 2-methylhydroxylation constituted a considerably larger proportion of overall ATX biotransformation in the PM group. Individual data points are color-coded by genotype (PM, red; IM, yellow; EM1, green; EM2, blue), and the size of the circles represent the apparent oral clearance relative to the largest apparent oral clearance in an individual with three functional CYP2D6 alleles (black symbol); NDA was not detected in the urine of this participant. The extremely small size of the PM data points relative to the reference demonstrates that the increased contribution of 2-hydroxylation in PMs does not “compensate” for the absence of CYP2D6 activity.

Figure 4

Simulated atomoxetine plasma concentration-time profiles for each study participant over the first 10 days of treatment with the current maximum FDA-recommended dose of 1.4 mg/kg up to 100 mg/d. A. The dashed line represents the threshold for therapeutic benefit proposed by Michelson et al. Plasma concentration profiles are color-coded for the genotype-stratified groups: PM (red), IM (yellow), EM1 (green) and EM2 (blue). The one participant with a CYP2D6 activity score of 3 (three functional alleles) included in the EM2 group is represented by the black profile. B. The gray shaded area in panel A is expanded to demonstrate that at steady state, only five study participants would exceed the proposed 800 ng/ml (~3.1 μM) threshold for any appreciable period of time under current FDA-approved dosing guidelines. Ordinate axes are provided for interconversion of ng/ml and μM units.