Beyond The Abstract Effect Of Tolterodine On Sleep Structure Modulated By CYP2D6 Genotype

Main Category: Sleep / Sleep Disorders / Insomnia
Also Included In: Neurology / Neuroscience;  Clinical Trials / Drug Trials
Article Date: 10 Dec 2007 - 0:00 PDT

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UroToday.com - Our new study1 presents a novel genotyping analysis of data recorded in two previous studies on the effect of tolterodine on sleep in healthy sleepers2,3. In the previous studies we have found a significant decrease of REM sleep when applying single doses of tolterodine compared to placebo2. This effect was more pronounced in healthy volunteers above the age of 50 years3 when compared to young healthy volunteers.

The new study aimed to investigate whether tolterodine related effects on sleep structure could be further explained by a different CYP2D6 metabolizer status. For this purpose we pooled the data from the two earlier studies in a retrospective analysis and were able to use 44 volunteers in total. Analyses for the CYP2D6 alleles 3, 4, 5, 6 and the duplication were performed. We found 19 extensive metabolizer carrying two active alleles of CYP2D6, 20 intermediate metabolizers carrying one deficient allele, 4 poor metabolizers carrying two deficient alleles, and one ultrareapid metabolizer carrying a CYP6D2 gene duplication combined with a wild-type allele.

The analysis revealed a significant reduction of REM sleep duration in the group carrying one or more deficient alleles (i.e. in intermediate and poor metabolizers). Additionally, in the poor metabolizers all 4 subjects showed a reduction of REM sleep. The clinical significant REM sleep reduction in the described subgroup might explain some of the reported side effects such as sleepiness although no significant differences between the subgroups related to this subjective sleep parameter was observed. We have to confess that our subgroup analysis suffers from the small sample size and this limits the interpretation of our results somewhat. In order to have enough poor metabolizers a much larger study would be needed and only then final conclusions could be drawn if the metabolizer status can conclusively explain the side effect of sleepiness in subjects taking tolterodine.

1. References Diefenbach K, Jaeger K, Wollny A, Penzel T, Fietze I, Roots I. Effect of tolterodine on sleep structure modulated by CYP2D6 genotype. Sleep Medicine (2007) doi:10.1016/j.sleep.2007.07.019 (article in press).

2. Diefenbach K, Donath F, Maurer A, Quispe Bravo S, Wernecke KD, Schwantes U, Haselmann J, Roots I. Randomised, double-blind study of the effects of oxybutynin, tolterodine, trospium chloride and placebo on sleep in healthy young volunteers. Clin Drug Invest 23: 395-404 (2003).

3. Diefenbach K, Arold G, Wollny A, Schwantes U, Haselmann J, Roots I. Effects on sleep of anticholinergics used for overactive bladder treatment in healthy volunteers aged >= 50 years. BJU International 95: 346-349 (2005).

Written by Konstanze Diefenbach, MD, Katrin Jaeger, MD, Agnes Wollny, MD, Thomas Penzel, MD, Ingo Fietze, MD, and Ivar Roots, MD, as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Link to full Abstract

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