Médication non-stimulante

1: Clin Pharmacokinet. 2005;44(6):571-90.  

Clinical pharmacokinetics of atomoxetine.
Sauer JM, Ring BJ, Witcher JW.

Elan Pharmaceuticals, Inc., South San Francisco, California, USA.

Atomoxetine (Strattera, a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine.The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1-2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.

PMID: 15910008 [PubMed - indexed for MEDLINE]
 

2: Expert Opin Drug Saf. 2005 Mar;4(2):311-21.

 

The safety of non-stimulant agents for the treatment of attention-deficit hyperactivity disorder.
Himpel S, Banaschewski T, Heise CA, Rothenberger A.

University of Goettingen, Department of Child and Adolescent Psychiatry, von-Siebold-Str. 5, 37075 Goettingen, Germany.

Due to their well-established efficacy and safety, stimulants are the drugs of first choice if medication for attention-deficit hyperactivity disorder (ADHD) is required. Nevertheless, for some individuals other, non-stimulant treatments are needed for several reasons. If so, atomoxetine is recommended as a second-line treatment. In addition, several tricyclic antidepressants, such as desipramine or imipramine, as well as alpha-2 agonists, especially clonidine or bupropion, might be efficient in treating ADHD, in particular in specific co-morbid conditions. Despite the fact that non-stimulant treatments in ADHD are usually well-tolerated with side effects being mostly moderate and transient, special safety aspects and precautions, specific for each drug, have to be considered whenever a non-stimulant treatment is chosen. This review focuses on the tolerability, occurrence of adverse events, precautions required to prevent severe adverse events, and essential pharmacological interaction in the treatment of ADHD symptoms by non-stimulants.
 PMID: 15794722 [PubMed - in process]

 

3: Expert Opin Emerg Drugs. 2004 Nov;9(2):293-302.  

New drugs for the treatment of attention-deficit/hyperactivity disorder.
Pataki CS, Feinberg DT, McGough JJ.

UCLA Neuropsychiatric Institute, Room 27-370C, 760 Westwood Plaza, Los Angeles, CA 90024, USA. cpataki@mednet.ucla.edu.

Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder of childhood. Recent research indicates that ADHD most often persists into adolescence and adulthood, and is associated with impairments in academic, social and occupational functioning. The ADHD diagnosis is based on history and clinical examination. There are no objective laboratory measures for diagnosis. ADHD is largely heritable. Its underlying pathophysiology has been theorised to include dysregulation of inhibitory noradrenergic frontocortical activity on dopaminergic striatal structures. Evidence shows that ADHD is highly responsive to pharmacological treatments resulting in global functional improvements. Although pharmacotherapy is recognised as the most effective treatment, additional components to optimise ADHD management include proper educational placement, parent management training and social skills development. Central nervous system stimulants, specifically methylphenidate and amphetamine, remain first-line pharmacological treatments. Atomoxetine, a selective noradrenergic re-uptake inhibitor, is the first non-stimulant compound to receive FDA approval for paediatric and adult ADHD. Other medication classes, including alpha-agonist antihypertensives, tricyclic antidepressants, other antidepressants such as buproprion, and the wake-promoting agent modafinil, are prescribed in off-label therapy. Ongoing development of new ADHD medications is expected to emphasise alternative and extended-release delivery systems and non-stimulant compounds.

PMID: 15571486 [PubMed - in process]

 
3: Ann Pharmacother. 2006 Sep 5; [Epub ahead of print]  
 
Use of Modafinil for the Treatment of Attention Deficit/Hyperactivity Disorder (October).

Lindsay SE, Gudelsky GA, Heaton PC.

College of Pharmacy, University of Cincinnati, Cincinnati, OH.

OBJECTIVE: To review the evidence for the use of modafinil in the treatment of attention deficit/hyperactivity disorder (ADHD). DATA SOURCES: A MEDLINE search (January 1990-May 2006) was conducted using MeSH terms ADHD and modafinil. The search was limited to English-language articles on clinical trials in humans. The Cochrane Database was also searched. STUDY SELECTION AND DATA EXTRACTION: The literature search yielded 4 randomized clinical trials. DATA SYNTHESIS: The use of modafinil in the treatment of ADHD is associated with significant improvements in primary outcome measures used to assess the status of patients diagnosed with ADHD. Several aspects of cognitive function in ADHD patients also appear to improve following modafinil treatment. Modafinil shows a favorable adverse effect profile. Insomnia and headache were the most common adverse effects, seen in approximately 20% of treated individuals. However, it has not been demonstrated that the beneficial effects of modafinil are maintained with chronic administration.

CONCLUSIONS: Modafinil may be a viable option for some patients in the treatment of ADHD, perhaps those for whom standard ADHD therapies have not been successful or tolerated. There remains a need for additional large, long-term studies using flexible titration methods to optimize the dose of modafinil to establish safety and efficacy, as well as head-to-head comparisons between modafinil and both long- and short-acting stimulants to determine the role of modafinil in the treatment of ADHD.

PMID: 16954326 [PubMed - as supplied by publisher]