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 ADHD were stratified by CYP2D6 genotype into groups with 0 (PM, n=4), 0.5 (IM, n=3), one (EM1, n=8) or two (EM2, n=8) functional alleles) and administered a single 0.5 mg/kg oral dose of atomoxetine. Plasma and urine samples were collected for 24 (IM, EM1 and EM2) or 72 hours (PMs). Dose-corrected atomoxetine systemic exposure (AUC0-∞) 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 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.

Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children

“…Although a predominant role for CYP2D6 in the disposition of ATX has been documented by several studies both in vitro (Ring et al, 2002) and in vivo Cui et al, 2007;Matsui et al, 2012;Brown et al, 2015), other factors also contribute to variability in the dose-exposure relationship, because two-to fivefold variability in apparent oral clearance can be observed within a CYP2D6 genotypepredicted phenotype group in vivo (Matsui et al, 2012;Brown et al, 2015). The objectives of this investigation were threefold: 1) investigate the sources of variability in ATX biotransformation within a CYP2D6 genotype/activity score group; 2) identify other CYP isoforms contributing to ATX biotransformation, particularly in the scenario of lower CYP2D6 activity; and 3) characterize the relative contribution of all pathways of ATX metabolism in a pediatric context, where the influences of CYP genotype, maturation, and development may be evaluated.…”

“…A recent review concluded that considerable time is needed to achieve a therapeutic response, which can be a frustrating period for patients and their families (Savill et al, 2015). A CYP2D6 genotype-stratified pharmacokinetic study of ATX conducted by our group (Brown et al, 2015) revealed an 11.4-fold difference in mean dose-corrected AUCs between CYP2D6 PMs and EMs. More importantly, there was a 30-fold range in dose-corrected AUC values among all participants given nominally the same dose.…”

Case report: Cytochrome P450 implications for comorbid ADHD and OCD pharmacotherapy

“…This pharmacotherapy combination increases the risk for adverse side effects, especially for CYP2D6 PMs. In effect, fluoxetine would increase the plasma level of atomoxetine by inhibiting CYP2D6 and CYP2C19 metabolism (Gold Standard, ; Brown et al., ). CYP2D6 may also be inhibited by other pharmaceuticals; especially strong inhibitors include: fluoxetine, paroxetine, quinidine, bupropion, and cinacalcet.…”

Challenges and Opportunities for Increasing the Knowledge Base Related to Drug Biotransformation and Pharmacokinetics during Growth and Development

“…Following up on the results of a PK study of atomoxetine in children with attention-deficit/hyperactivity disorder (Brown et al, 2016), Dinh et al (2016) characterized the P540 enzymes responsible for 4-hydroxylation in CYP2D6 poor metabolizers as well as the formation of the 29-methylhydroxyl metabolite, which was observed to account for a greater proportion of atomoxetine biotransformation in the presence of decreased CYP2D6 activity. CYP2E1 and CYP3A were determined to contribute to 49-hydroxy atomoxetine formation in livers with CYP2D6 intermediate and poor metabolizer status, and CYP2B6 was primarily responsible for 29-methylhydroxy atomoxetine formation.…”