Atomoxetine Other names: (R)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine

Atomoxetine is a highly selective and potent inhibitor of the pre-synaptic noradrenaline transporter, its presumed mechanism of action, without directly affecting the serotonin or dopamine transporters. Atomoxetine has minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors.

Atomoxetine has two major oxidative metabolites: 4-hydroxyatomoxetine and N-desmethylatomoxetine.

4-hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the noradrenaline transporter but, unlike atomoxetine, this metabolite also exerts some inhibitory activity at the serotonin transporter. However, any effect on this transporter is likely to be minimal, as the majority of 4-hydroxyatomoxetine is further metabolised such that it circulates in plasma at much lower concentrations (1% of atomoxetine concentration in extensive metabolisers and 0.1% of atomoxetine concentration in poor metabolisers).

N-desmethylatomoxetine has substantially less pharmacological activity compared with atomoxetine. It circulates in plasma at lower concentrations in extensive metabolisers and at comparable concentrations to the parent drug in poor metabolisers at steady-state.

Atomoxetine is not a psychostimulant and is not an amphetamine derivative. In a randomised, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine and placebo, atomoxetine was not associated with a pattern of response that suggested stimulant or euphoriant properties.

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under six years of age.

Pharmacokinetic studies have shown that atomoxetine capsules and oral solution are bioequivalent.

Absorption: Atomoxetine is rapidly and almost completely absorbed after oral administration, reaching mean maximal observed plasma concentration (C_max) approximately 1 to 2 hours after dosing. The absolute bioavailability of atomoxetine following oral administration ranged from 63% to 94%, depending upon inter-individual differences in the modest first-pass metabolism. Atomoxetine can be administered with or without food.

Distribution

Atomoxetine is widely distributed and is extensively (98%) bound to plasma proteins, primarily albumin.

Biotransformation

Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. Individuals with reduced activity of this pathway (poor metabolisers) represent about 7% of the Caucasian population and have higher plasma concentrations of atomoxetine compared with people with normal activity (extensive metabolisers). For poor metabolisers, AUC of atomoxetine is approximately 10-fold greater and Css,max is about 5-fold greater than extensive metabolisers. The major oxidative metabolite formed is 4-hydroxyatomoxetine that is rapidly glucuronidated. 4-hydroxyatomoxetine is equipotent to atomoxetine but circulates in plasma at much lower concentrations. Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. Atomoxetine does not inhibit or induce CYP2D6 at therapeutic doses.

Cytochrome P450 Enzymes

Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

Elimination

The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in extensive metabolisers and 21 hours in poor metabolisers. Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine.

Linearity/non-linearity

Pharmacokinetics of atomoxetine are linear over the range of doses studied in both extensive and poor metabolisers.

Special populations

Hepatic impairment results in a reduced atomoxetine clearance, increased atomoxetine exposure (AUC increased 2-fold in moderate impairment and 4-fold in severe impairment), and a prolonged half-life of parent drug compared to healthy controls with the same CYP2D6 extensive metaboliser genotype. In patients with moderate to severe hepatic impairment (Child-Pugh class B and C) initial and target doses should be adjusted).

Atomoxetine mean plasma concentrations for end-stage renal disease (ESRD) subjects were generally higher than the mean for healthy control subjects shown by C_max (7% difference) and AUC_0-∞ (about 65% difference) increases. After adjustment for body weight, the differences between the two groups are minimised. Pharmacokinetics of atomoxetine and its metabolites in individuals with ESRD suggest that no dose adjustment would be necessary.

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, or reproduction and development. Due to the dose limitation imposed by the clinical (or exaggerated pharmacological) response of the animals to the drug combined with metabolic differences among species, maximum tolerated doses in animals used in non-clinical studies produced atomoxetine exposures similar to or slightly above those that are achieved in CYP2D6 poor metabolising patients at the maximum recommended daily dose.

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioural and sexual development. Slight delays in onset of vaginal patency (all doses) and preputial separation (≥10mg/kg/day), and slight decreases in epididymal weight and sperm number (≥10mg/kg/day) were seen; however, there were no effects on fertility or reproductive performance. The significance of these findings to humans is unknown.

Pregnant rabbits were treated with up to 100mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, decrease in live foetuses, increase in early resorption, slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The incidence of these findings is within historical control values. The no-effect dose for these findings was 30mg/kg/day. Exposure (AUC) to unbound atomoxetine in rabbits, at 100mg/kg/day, was approximately 3.3-times (CYP2D6 extensive metabolisers) and 0.4-times (CYP2D6 poor metabolisers) those in humans at the maximum daily dose of 1.4mg/kg/day. The findings in one of three rabbit studies were equivocal and the relevance to man is unknown.