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STRATTERA (ATOMOXETINE HCL): CLINICAL PHARMACOLOGY
Mechanism of Action
The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies.
An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored. The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline.
Atomoxetine (Strattera) is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. 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.
The pharmacokinetics of Atomoxetine (Strattera) capsules have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, Cmax, and AUC values were observed in children, adolescents, and adults. Clearance and volume of distribution after adjustment for body weight were also similar.
Absorption and distribution
Atomoxetine HCl (Strattera) is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing.
Atomoxetine HCl (Strattera) capsules can be administered with or without food. Administration of Atomoxetine Hydrochloride (Strattera) with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower Cmax, and delayed Tmax by 3 hours. In clinical trials with children and adolescents, administration of Atomoxetine Hydrochloride (Strattera) capsules with food resulted in a 9% lower Cmax.
The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating that atomoxetine distributes primarily into total body water. Volume of distribution is similar across the patient weight range after normalizing for body weight.
At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.
Metabolism and elimination
Strattera (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 (Atomoxetine) capsules 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. Atomoxetine did not inhibit or induce the CYP2D6 pathway.
The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).
Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N594
desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).
Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction of the Strattera (Atomoxetine HCl) dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.
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