Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Abstract

Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children ( ‡6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.

Evaluation of the Potential Pharmacokinetic Interaction between Atomoxetine and Fluvoxamine in Healthy Volunteers

“…The primary metabolite, 4-hydroxyatomoxetine, is formed after aromatic ring-hydroxylation of the parent drug, a process mediated by CYP2D6, and is subsequently glucuronidated and eliminated in the urine. ATX and 4-hydroxyatomoxetine showed similar pharmacological activities [4,5] . The pharmacokinetics is influenced by CYP2D6 polymorphism, as 8-to 10-fold differences were seen in ATX pharmacokinetics between the 2 phenotypic groups [5] .…”

“…ATX and 4-hydroxyatomoxetine showed similar pharmacological activities [4,5] . The pharmacokinetics is influenced by CYP2D6 polymorphism, as 8-to 10-fold differences were seen in ATX pharmacokinetics between the 2 phenotypic groups [5] . More specifically, mean plasma concentrations that were approximately 10-fold higher were encountered in PMs in comparison to EMs.…”

Atomoxetine Induced Obsessive-Compulsive Disorder

“…Atomoxetine, a nonstimulant drug used in the treatment of ADHD, is the selective blocker of presynaptic norepinephrine carriers in the central nervous system. 3 There are reports that the use of atomoxetine in the presence of depression, anxiety, tic disorder, or nocturnal enuresis coexisting with ADHD has possible advantages. [8][9][10] The use of atomoxetine is known to cause side effects such as headache, sleep disorders, increases in blood pressure, cardiac problems, suicidal tendencies, and restlessness.…”

“…It was the first non-stimulant medication to receive FDA approval for the treatment of ADHD. 3 In this article, a case in which atomoxetine was initiated due to ADHD and OCD developed during the treatment is reported.…”

Codeine Pharmacogenetics as a Proof of Concept for Pediatric Precision Medicine

“…5 Therefore, safe and effective use of this medication will require dosing adjustment based in part on pharmacogenetic data. 6 Hospital research networks are beginning to test broader incorporation of pharmacogenomic data into pediatric electronic health records and clinical decision support. 7,8 Of the ~1000 drugs approved by the FDA, nearly 100 are candidates for pharmacogenetic testing in light of population variability in 12 genes.…”