Post by Amtram on Feb 12, 2014 16:52:48 GMT -5
The meta-analysis is here, free full text version. Here are the relevant parts:
Pharmacodynamics
Atomoxetine is a potent norepinephrine (NE) uptake inhibitor in vitro and in vivo with relatively low affinity for 5-HT and DA uptake sites;4,5 it has 290-fold lower affinity for dopamine transporters than norepinephrine.6 Mechanistically, inhibition of the NE transporter blocks synaptic clearance of NE, thereby increasing synaptic NE concentrations in noradrenergic pathways. For example, NE in prefrontal cortical (PFC) regions has been shown to play a key role in attention and higher cognitive processes.
In animal studies, atomoxetine has been shown to selectively increase dopamine (DA) to a similar magnitude as NE in the PFC, due to region-specific shared monoamine uptake inhibition, while not altering DA in other dopamine-rich brain regions such as nucleus accumbens and striatum.6 In addition, atomoxetine robustly increased NE in other brain regions with a substantial density of norepinephrine transporters; atomoxetine rapidly and persistently increased norepinephrine in rat occipital cortex, lateral hypothalamus, dorsal hippocampus, and cerebellum.
Pharmacokinetics
Absorption and distribution
Atomoxetine is efficiently absorbed after oral administration (range 63%–94%); its bioavailability is minimally affected by food. After oral administration, atomoxetine reaches a maximum plasma concentration in approximately 1 to 2 hours. Atomoxetine is highly protein bound, roughly 98%, specifically to albumin.
Metabolism and elimination
There are three metabolic pathways involved in the clearance of atomoxetine; aromatic ring-hydroxylation, benzylic hydroxylation, and N-demethylation. The hepatic enzyme cytochrome P450 2D6 (CYP2D6) is the primary metabolic pathway for atomoxetine, yielding its primary oxidative metabolite 4-hydroxyatomoxetine. Over 80% of the atomoxetine dose is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide in the urine, with a minority excreted in the feces. It is well known that there are distinct differences within populations of CYP2D6 activity (extensive versus poor metabolizers), and that genetic tests are presently available to identify this variability. Those persons who are deemed “poor metabolizers” (PM) of CYP2D6 drugs (about 7% of the Caucasian population) have been shown to have mean peak atomoxetine concentrations up to 5-fold higher and total plasma exposure of atomoxetine 10-fold higher than persons who have extensive (normal) metabolic (EM) activity. Atomoxetine has a plasma half-life of about 5.2 hours in extensive metabolizers, compared to 22 hours in poor metabolizers, as atomoxetine is metabolized through several alternative CYP pathways. From a clinical standpoint, the important question is: what is the practical impact of CYP metabolism status on the treatment of a given patient? A recent pooled analysis addressed this question by examining the relationship between CYP2D6 status and clinical response in children and adolescents with ADHD. Efficacy data were derived from 6 acute clinical trials (N = 559 EMs, 30 PMs), while safety and tolerability data was assessed using a pooled database from 14 studies (N = 3017 EMs, 237 PMs). Efficacy analyses demonstrated significantly greater improvements in ADHD rating scale scores and rates of response in PMs as compared to EMs (80% and 59% response rates in PMs and EMs respectively). However, the pooled efficacy and PK data found a low (0.179) correlation coefficient between response and peak concentration; the differential efficacy between EMs and PMs may instead be related to total plasma atomoxetine exposure or area under the curve (AUC). In this same analysis, reduced appetite, insomnia and tremor were seen in significantly greater rates in PMs, compared to EMs. In addition, significantly greater increases in mean pulse rate at endpoint (+3.9 bpm) and in mean diastolic blood pressure (DBP) at endpoint (+1.6 mmHg) were observed in PMs, as compared to EMs. The authors suggest that these differences may be due to increased noradrenergic tone in PM and/or due to persistent effects due to more constant drug concentrations throughout the day.
Since atomoxetine is highly protein bound, systemic clearance of atomoxetine may be significantly reduced in those patients with hepatic impairment. Dosage adjustment is recommended in these patients.
Essentially, this means that Strattera is almost exclusively a norepinephrine reuptake inhibitor, can be taken without dietary restrictions, and is processed through the liver. People who have liver disease or are poor metabolizers may need to take a different dose.
Pharmacodynamics
Atomoxetine is a potent norepinephrine (NE) uptake inhibitor in vitro and in vivo with relatively low affinity for 5-HT and DA uptake sites;4,5 it has 290-fold lower affinity for dopamine transporters than norepinephrine.6 Mechanistically, inhibition of the NE transporter blocks synaptic clearance of NE, thereby increasing synaptic NE concentrations in noradrenergic pathways. For example, NE in prefrontal cortical (PFC) regions has been shown to play a key role in attention and higher cognitive processes.
In animal studies, atomoxetine has been shown to selectively increase dopamine (DA) to a similar magnitude as NE in the PFC, due to region-specific shared monoamine uptake inhibition, while not altering DA in other dopamine-rich brain regions such as nucleus accumbens and striatum.6 In addition, atomoxetine robustly increased NE in other brain regions with a substantial density of norepinephrine transporters; atomoxetine rapidly and persistently increased norepinephrine in rat occipital cortex, lateral hypothalamus, dorsal hippocampus, and cerebellum.
Pharmacokinetics
Absorption and distribution
Atomoxetine is efficiently absorbed after oral administration (range 63%–94%); its bioavailability is minimally affected by food. After oral administration, atomoxetine reaches a maximum plasma concentration in approximately 1 to 2 hours. Atomoxetine is highly protein bound, roughly 98%, specifically to albumin.
Metabolism and elimination
There are three metabolic pathways involved in the clearance of atomoxetine; aromatic ring-hydroxylation, benzylic hydroxylation, and N-demethylation. The hepatic enzyme cytochrome P450 2D6 (CYP2D6) is the primary metabolic pathway for atomoxetine, yielding its primary oxidative metabolite 4-hydroxyatomoxetine. Over 80% of the atomoxetine dose is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide in the urine, with a minority excreted in the feces. It is well known that there are distinct differences within populations of CYP2D6 activity (extensive versus poor metabolizers), and that genetic tests are presently available to identify this variability. Those persons who are deemed “poor metabolizers” (PM) of CYP2D6 drugs (about 7% of the Caucasian population) have been shown to have mean peak atomoxetine concentrations up to 5-fold higher and total plasma exposure of atomoxetine 10-fold higher than persons who have extensive (normal) metabolic (EM) activity. Atomoxetine has a plasma half-life of about 5.2 hours in extensive metabolizers, compared to 22 hours in poor metabolizers, as atomoxetine is metabolized through several alternative CYP pathways. From a clinical standpoint, the important question is: what is the practical impact of CYP metabolism status on the treatment of a given patient? A recent pooled analysis addressed this question by examining the relationship between CYP2D6 status and clinical response in children and adolescents with ADHD. Efficacy data were derived from 6 acute clinical trials (N = 559 EMs, 30 PMs), while safety and tolerability data was assessed using a pooled database from 14 studies (N = 3017 EMs, 237 PMs). Efficacy analyses demonstrated significantly greater improvements in ADHD rating scale scores and rates of response in PMs as compared to EMs (80% and 59% response rates in PMs and EMs respectively). However, the pooled efficacy and PK data found a low (0.179) correlation coefficient between response and peak concentration; the differential efficacy between EMs and PMs may instead be related to total plasma atomoxetine exposure or area under the curve (AUC). In this same analysis, reduced appetite, insomnia and tremor were seen in significantly greater rates in PMs, compared to EMs. In addition, significantly greater increases in mean pulse rate at endpoint (+3.9 bpm) and in mean diastolic blood pressure (DBP) at endpoint (+1.6 mmHg) were observed in PMs, as compared to EMs. The authors suggest that these differences may be due to increased noradrenergic tone in PM and/or due to persistent effects due to more constant drug concentrations throughout the day.
Since atomoxetine is highly protein bound, systemic clearance of atomoxetine may be significantly reduced in those patients with hepatic impairment. Dosage adjustment is recommended in these patients.
Essentially, this means that Strattera is almost exclusively a norepinephrine reuptake inhibitor, can be taken without dietary restrictions, and is processed through the liver. People who have liver disease or are poor metabolizers may need to take a different dose.