PM can have up to ten times higher mean serum concentrations than EM the half-life can increase four to five times (Sauer et al. The two CYP polymorphisms lead to clinically relevant differences in the pharmacokinetics of atomoxetine. More than 90% of all individuals, the so-called EM, show a normal activity of CYP2D6 (Sauer et al. Regarding the activity of CYP2D6, "extensive metabolizers" (EM) and "poor metabolizers" (PM) can be distinguished. The influence of CYP2C19 on the metabolism of atomoxetine is estimated to be small (Sauer et al. The side metabolite N-desmethylatomoxetine is mainly catalyzed by CYP2C19 (Ring et al. The metabolism of atomoxetine to the main metabolite 4-hydroxyatomoxetine is primarily mediated by CYP2D6 (Ring et al. With regard to genetic polymorphisms and their influence on the metabolism of atomoxetine, the main focus is on cytochrome P450 enzymes (CYP enzymes), whose activity can be altered by such polymorphisms. Not only parameters such as age, comorbidities, comedications, compliance and smoking, but also genetic polymorphisms can have an influence on pharmacokinetics (Paulzen et al. However, there are interindividual differences in the pharmacokinetics of atomoxetine fluctuations in serum concentrations and a different therapeutic response may be the consequence (Hiemke et al. Almost one third of the children who initially received methylphenidate and later on atomoxetine, responded selectively better to one of the two drugs (Newcorn et al.
If a therapy with psychostimulants is not sufficiently effective, if side effects occur, contraindications exist or if coexisting disorders are present, a guideline-based therapy considers atomoxetine to be a second-best choice following methylphenidate (Lilly Deutschland Gmbh 2015 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften 2017 National Institute for Health and Care Excellence 2018). Compared to placebo, atomoxetine shows a significantly stronger effect in terms of symptom reduction and improvement of functional abilities in children and adolescents with ADHD (Michelson et al.
2005 Briars and Todd 2016 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften 2017 Falkai et al. However, due to good efficacy and tolerability an exact reference range remained difficult to determine.Ītomoxetine is a selective norepinephrine reuptake inhibitor (NARI) and is potentially among the first-line pharmacotherapy options in the treatment of attention-deficit hyperactivity disorder (ADHD), one of the most common psychiatric disorders in children and adolescents (Wong et al. The preliminary therapeutic reference range for children and adolescents proved to be narrower than the reference range for adult patients. Therefore, and due to a limited study population, the results have to be regarded as preliminary observations that must be confirmed in further studies. A preliminary therapeutic reference range was between 100 and 400 ng/ml. The efficacy as well as the tolerability proved to be mainly moderate or significant. In this time interval, a significant correlation between the weight-normalized dose and the serum concentrations was found. As part of TDM, a time interval with maximum concentrations of 1–3 h after the administration of atomoxetine was determined for blood sampling.
Therapeutic effectiveness and side effects were evaluated according to the categories “low”, “moderate”, and “significant”. Using the analytical method of high-performance liquid chromatography with UV detection, 94 serum concentrations of 74 patients between 6 and 21 years of age were determined. The aim of this retrospective pharmacokinetic–pharmacodynamic analysis was to derive age-appropriate recommendations for the implementation of TDM to improve the efficacy and tolerability of atomoxetine in children and adolescents. Therapeutic drug monitoring (TDM) with the quantification and interpretation of atomoxetine serum concentrations is used to determine an individual dose followed by an optimal effectiveness and minimal side effects. The selective norepinephrine reuptake inhibitor atomoxetine is potentially among the first-line pharmacotherapy options for ADHD.
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