Atomoxetine

Pharmacogenomic Information in the Context of the FDA-Approved Drug Label*

Atomoxetine is a selective noradrenaline reuptake inhibitor. It is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder. The exact mechanism of action is unknown, but atomoxetine selectively inhibits the pre-synaptic noradrenaline transporter (SLC6A2), as determined in ex vivo studies.
Atomoxetine is eliminated primarily through oxidative metabolism by CYP2D6 and subsequent glucuronidation.

Excerpts from the Atomoxetine drug label:

"Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of STRATTERA with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary."

"A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity (extensive metabolizers (EMs)). Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure."

"In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. "

"Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of STRATTERA may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs."

(For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Atomoxetine drug label PDF.)