Peer-reviewed article

Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment

Ishtiak-Ahmed K, Lunenburg C, Thirstrup J, Clausen L, Thomsen P et al. · 1 Sept 2022

Abstract

Introduction Atomoxetine, a first-line treatment option for ADHD, is affected by pharmacogenetic (PGx) variation of the drug-metabolizing enzyme CYP2D6. Despite the recommendation of CYP2D6 testing, the use of PGx-guided dosing remains low in Denmark. Objectives We investigated wide-ranging clinical outcomes in atomoxetine users in association with PGx variability. Methods We analyzed 6,798 individuals (55% children) with a first prescription for atomoxetine identified from the Danish population-based iPSYCH case-cohort study linking biobank information with Danish registers. Individuals were categorized based on their single-nucleotide-polymorphism-based CYP2D6 genotype into normal (NM), intermediate (IM), and poor metabolizer (PM). Clinical outcomes included treatment switching, discontinuation, psychiatric inpatient-, outpatient-, and emergency contact, suicide attempt/self-harm, sleep problem, and depression. Individuals’ CYP2D6-status could change due to drug-drug-interactions of weak, intermediate, or strong-CYP2D6 inhibitors (phenoconversion), which we accounted for by time-varying phenotype assessment. Incidence rate ratios (IRR) were estimated using Poisson regression analyses and adjusted for a wide range of potential confounders and covariates. Results Over two-thirds of the individuals had a hospital diagnosis of ADHD at the first atomoxetine prescription. The distribution of CYP2D6 phenotypes was similar in children and adults. IM/PM children had a significantly higher risk of a sleeping problem compared with NM children (IRR 1.25, 95% CI 1.01-1.54). Compared with NM adults, those with IM/PM had a higher risk of switching (1.15, 95% CI 0.98-1.35). Conclusions This is the first study showing the potential impact of PGx variability on clinical outcomes of atomoxetine users in a population-based setting, highlighting the utility of PGx testing. Disclosure No significant relationships.