Selegiline Transdermal System: An Examination of the Potential for CYP450-Dependent Pharmacokinetic Interactions With 3 Psychotropic Medications

Mercer University, Атланта, Michigan, United States
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 03/2007; 47(2):146-58. DOI: 10.1177/0091270006296151
Source: PubMed


Selegiline transdermal system (STS) is a recently approved monoamine oxidase inhibitor antidepressant. This article reports results from 3 studies examining the potential for cytochrome P450-dependent pharmacokinetic interactions between STS and 3 psychotropic medications that might be coadministered. Three open-label, randomized, Latin square, 3-sequence crossover design studies were conducted with healthy volunteers to determine the pharmacokinetic parameters of STS 6 mg/24 h and test drug (alprazolam, olanzapine, or risperidone) when administered alone and concomitantly. All pharmacokinetic parameters of interest were unaltered following selegiline or test drug monotherapy when compared to concomitant therapy. This was confirmed by least squares mean ratios and their 90% confidence intervals of log(e)-transformed C(max) and AUC(tau) values, using either standard bioequivalence criteria of 80% to 125% or study-defined 70% to 143% boundary criteria. These results demonstrate that STS 6 mg/24 h may provide an antidepressant option that is unlikely to result in CYP450-mediated pharmacokinetic drug-drug interactions.

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Available from: Albert Azzaro, Jun 03, 2014
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    • "Experimental studies fail to show signifi cant drug–drug interactions between STS and psychotropic drugs such as olanzapine, risperidone, and alprazolam, that are CYP1A2, 2D6 and 3A4 substrates, respectively (Azzaro et al 2007b). This may be an important feature as a majority of patients diagnosed with MDD also meet criteria for an additional psychiatric diagnosis (Kessler et al 2003) and may be co-prescribed other psychotropic medications that are CYP450 substrates. "
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    ABSTRACT: Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects. In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD). Currently, the use of orally administered MAO inhibitor antidepressants (eg, phenelzine, tranylcypromine) is limited by the risk of tyramine-provoked events (eg, acute hypertension and headache, also known as the "cheese reaction") when combined with dietary tyramine. The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours. Delivery of selegiline transdermally (EMSAM((R))) bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect. At dosages of 6-12 mg/24 hours, EMSAM has been shown to improve symptoms of depression, have good tolerability, and have high rates of medication adherence. However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of tyramine intake is recommended. The introduction of EMSAM overcomes many of the safety concerns affiliated with the conventional oral MAO inhibitors and EMSAM may be considered another strategy for the treatment of MDD, especially in patients who cannot tolerate oral antidepressants, are poorly adherent, who present with atypical depressive symptoms, or have failed other antidepressants.
    Full-text · Article · Nov 2007 · Neuropsychiatric Disease and Treatment
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    ABSTRACT: Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol-defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.
    Full-text · Article · Sep 2007 · The Journal of Clinical Pharmacology
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    ABSTRACT: Selegiline is a selective irreversible inhibitor of monoamine oxidase (MAO)-B during lowdose oral treatment. Additional MAO-A inhibition occurs in higher dose ranges. Selegiline transdermal system (STS) shows a more potent MAO inhibition in comparison with orally administered selegiline, and at minimum doses of 20 mg/20 cm2 patch delivering 6 mg/24 h, no dietary restrictions, including low-tyramine food, are. necessary. While oral selegiline has been used for years in the treatment of Parkinson's disease, the US FDA recently approved the STS for use in treating major depression. Data from three randomized controlled trials showed a significantly better efficacy of STS in the treatment of unipolar major depression in comparison with placebo during 6-8 weeks of treatmerit In addition, one long-term randomized controlled trial demonstrated the efficacy of the STS in relapse prevention of unipolar depression over 1 year. A total humber of 515 depressed patients received STS during these studies. The tolerability profile of STS without dietary restrictions was excellent. The only side effects that were more frequent than with placebo were application site reactions. No change in vital parameters and no hypertensive crisis have been recorded. Comparative studies including treatment with established antidepressants and the investigation of bipolar depressed patients and of specific patient subgroups (e.g., anergic and atypical depression) have to follow. The combination of the well-known effectiveness of Irreversible MAO inhibitors with a good tolerability profile and a new pharmaceutical form, possibly enhancing compliance, represents a promising further expansion of the pharmacotherapeutic repertoire in the treatment of depression.
    No preview · Article · Nov 2007 · Future Neurology
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