Clinical Pharmacokinetics of Atomoxetine

Abstract

Atomoxetine (Strattera, a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine. The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1-2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: a review

“…A recent meta-analysis reported the number-needed-to-treat (NNT) for atomoxetine treatment response (reduction of Ն25% in ADHD-RS total score from baseline) was 3.43 (95% CI, 2.79-4.45). 18 Signifi cant improvement compared with those treated with placebo has been demonstrated across efficacy measures, in younger (6-7 years) and older (8)(9)(10)(11)(12) However, overall in the treatment of pediatric ADHD, superior effect sizes are consistently observed with immediate-release and long-acting stimulants, as compared to non-stimulants, including atomoxetine. 20 …”

Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers

“…This agent is rapid and well-absorbed after oral administration and has a bioavailability that ranges from 63 to 94%. After oral intake, it reaches a peak plasma concentration in approximately 1 to 2 hours and is highly protein bound (~ 98-99 %) (3)(4)(5). Three pathways are involved in the metabolism of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and Ndemethylation.…”

“…Further transformation for this compound occurs via glucuronidation, resulting in 4-hydroxyatomoxetine-O-glucuronide (4,6). The polymorphism of CYP2D6 divides the individuals taking this nonstimulant medication in two groups, respectively extensive metabolizers (EMs -over 90% of the population) and poor metabolizers (PMs -approximately 7% of population) (3).…”

“…The polymorphism of CYP2D6 divides the individuals taking this nonstimulant medication in two groups, respectively extensive metabolizers (EMs -over 90% of the population) and poor metabolizers (PMs -approximately 7% of population) (3). As a result of a much slower hepatic metabolism, the average steady-state plasma _________________________________________ concentrations of atomoxetine are about 10-fold higher in PMs than in EMs (4). The mean plasma elimination half-lives (t 1/2 ) of atomoxetine and its active metabolite vary between the two populations.…”

“…The mean plasma elimination half-lives (t 1/2 ) of atomoxetine and its active metabolite vary between the two populations. In EMs, atomoxetine has a t 1/2 of 5.2 h and 4-hydroxyatomoxetine of 6-8 h, meanwhile, in PMs, the t 1/2 of the two compounds are 21 h for the parent drug and 19 h for its hydroxylated metabolite (3,4). The majority of the atomoxetine dose is excreted as a glucuronide conjugate in the urine (80%) and feces (18%), while less than 3 % is eliminated unchanged (1,3,4).…”