Atomoxetine, a Novel Treatment for Attention-Deficit-Hyperactivity Disorder

Alisa K. Christman, Pharm.D.; Joli D. Fermo, Pharm.D.; John S. Markowitz, Pharm.D.


Pharmacotherapy. 2004;24(8) 

In This Article

Pharmacokinetic Profile

Atomoxetine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. Significant differences are noted in the disposition of atomoxetine between extensive metabolizers of cytochrome P450 (CYP) 2D6 substrates and genetically poor metabolizers. For example, the absolute bioavailability of atomoxetine in extensive metabolizers is 63%, whereas the bioavailability in poor metabolizers is 94%.[16] In single- and multiple-dose studies, the maximum concentration (Cmax) of atomoxetine was reached in 1-2 hours after dosing in extensive metabolizers and 3-4 hours in poor metabolizers.[17,18]

The administration of atomoxetine after ingestion of a standardized high-fat meal did not affect the extent of absorption, but it did decrease the rate of absorption.[16] This resulted in a 37% lower Cmax and a delayed time to Cmax by approximately 3 hours.[16] In poor metabolizers, the steady-state concentration of atomoxetine in plasma is 3-fold higher with multiple doses compared with that with a single dose.[17] In pharmacokinetic studies comparing both once- and twice-daily dosing in extensive metabolizers, the steady-state profiles in patients who received twice-daily dosing were similar to those in patients who received once-daily dosing, indicating that peak plasma concentrations were not increased with twice-daily dosing.[18]

The distribution of atomoxetine is primarily into total body water, with a volume of distribution of 0.85 L/kg. Atomoxetine is approximately 98% protein bound, whereas the active metabolite 4-hydroxyatomoxetine is approximately 67% protein bound.[19]

The metabolic pathways of atomoxetine are depicted in Figure 1. Atomoxetine is metabolized predominantly in the liver by the CYP enzymes, primarily the CYP2D6 isoenzyme. The degree of CYP2D6 metabolism in children is similar to that in adults, indicating that maturation of the enzyme has reached adult competency in children aged 7-14 years.[18] The primary mechanism of clearance is by oxidative metabolism and glucoronidation in extensive metabolizers, based on several single- and multiple-dose pharmacokinetic studies.[16,19,20] Most metabolites are eliminated renally. There are three major phase 1 metabolic pathways that atomoxetine undergoes: aromatic ring hydroxylation, benzylic oxidation, and N-demethylation.[17,19] The primary phase 1 metabolite that is formed from the oxidative processes is 4-hydroxyatomoxetine, which is further conjugated to 4-hydroxyatomoxetine-O-glucuronide, the primary active metabolite of atomoxetine (Figure 1). The metabolite 4-hydroxyatomoxetine appears to be as pharmacologically active as the parent compound in terms of norepinephrine transport inhibition, with a decreased blockade of the serotonin transporter. However, in pediatric pharmacokinetic studies, levels of 4-hydroxyatomoxetine were very low compared with atomoxetine, suggesting that it has a minor role in norepinephrine transporter blockade after administration of atomoxetine.[18] Another phase 1 metabolite, N-desmethylatomoxetine, is formed by the enzymatic pathway CYP2C19 and is considerably less pharmacologically active than 4-hydroxyatomoxetine.[19] It therefore does not contribute significantly to the efficacy of atomoxetine. Low plasma concentrations were observed in extensive metabolizers, most likely because of the subsequent oxidative metabolism of N-desmethylatomoxetine.[19] However, if the rate of metabolic oxidation is slowed, the primary pathway for elimination is through N-demethylation, resulting in accumulation of N-desmethylatomoxetine.[16,19,20]

The mean elimination half-life of atomoxetine after oral administration is 5.2 hours.[16] In poor metabolizers, the mean elimination half-life is 21.6 hours, a result of reduced clearance of atomoxetine ( Table 1 ). This results in an area under the concentration-time curve (AUC) that is about 10-fold greater and a steady-state Cmax that is approximately 5-fold greater than those of extensive metabolizers.[16] The elimination half-life of the metabolite 4-hydroxyatomoxetine is 6-8 hours in extensive metabolizers, whereas the elimination half-life of N-desmethylatomoxetine is 34-40 hours in poor metabolizers.[16] Greater than 80% of the dose of atomoxetine is excreted primarily in the urine as 4-hydroxyatomoxetine. Seventeen percent of the total dose is excreted through the feces. Less than 3% of the dose is excreted unchanged, indicating extensive biotransformation.[16]

Extensive versus Poor Metabolizers. Results of studies performed in healthy adults indicate that the pharmacokinetics of atomoxetine are influenced by the genetic polymorphism of CYP2D6.[19] Atomoxetine undergoes bimodal distribution with two distinct populations that are characteristic of the CYP2D6 enzyme: extensive metabolizers and poor metabolizers.[17,19,20] Only 7% of the Caucasian population and less than 1% of the Asian population are considered poor metabolizers.[21] These individuals have either a mutation or a deletion of the CYP2D6 gene; therefore, efficient metabolism of CYP2D6 substrates is not achieved. Patients who may be suspected of being poor metabolizers are identified through genotyping procedures that specify metabolic status.

The circulating plasma concentrations of 4-hydroxyatomoxetine may vary at about 1% of the atomoxetine concentration in extensive metabolizers and 0.1% of the atomoxetine concentration in poor metabolizers.[16] Although 4-hydroxyatomoxetine is formed primarily by CYP2D6 in poor metabolizers, the metabolite also may be formed by other enzymatic pathways.[20,22] There is a potential for drug accumulation during multiple dosing in patients who show the polymorphic characteristic of poor metabolizers. Pharmacokinetic studies indicate that individuals who are poor metabolizers display a higher steady-state concentration of atomoxetine and N-desmethylatomoxetine than that of extensive metabolizers.[18]

In a single-dose pharmacokinetic study conducted in extensive metabolizers, in which the atomoxetine dose was 10 mg, the plasma concentrations and AUC values of the metabolites were much lower than the atomoxetine concentration.[18] Even though the concentration of 4-hydroxyatomoxetine was measurable in plasma, it was still 26 times less than the concentration of atomoxetine. In multiple-dose pharmacokinetic studies conducted in extensive metabolizers in which the dosage was 20-45 mg twice/day, the degree of accumulation of atomoxetine or its metabolites at steady-state concentrations was low, as the half-life, clearance, and volume of distribution were similar to those of single-dosing pharmacokinetics.[18] The plasma concentration of 4-hydroxyatomoxetine was 35 times lower than the concentration of atomoxetine. With combination of both the single- and multiple-dose pharmacokinetics, a linear regression analysis indicated that the concentration of atomoxetine in the plasma was proportionate to the dose and not related to the dosing schedule. As doses are increased on a mg/kg basis, the AUC for atomoxetine increases proportionately.