800 Pharmacokinetics of the rivastigmine patch reassurance that the treatment has been administered, thus potentially improving compliance (6,7). The rivastigmine patch is the ﬁrst transdermal treatment for AD, and another cholinesterase inhibi- tor is also being developed to deliver medication transdermally (8). Patches may have inherent advan- tages over conventional oral formulations, and it is interesting to consider how they might change the treatment paradigm. This article reviews the clinical features of patch therapy for dementia, compared with conventional oral administration. Challenges with orally administered cholinesterase inhibitors When a drug is administered orally, it is absorbed through the gastrointestinal wall, and plasma drug levels rise rapidly to their peak level (Cmax). Drug plasma levels then fall until the next dose is adminis- tered, at which point the plasma levels are at their lowest (Cmin). Larger and more frequent plasma ﬂuc- tuations are associated with an increased incidence of cholinergically mediated side effects, particularly gas- trointestinal AEs such as nausea and vomiting (2). By reducing Cmax and slowing the time that it takes to reach Cmax (tmax), the potential for these AEs may be reduced (2). Between Cmax and Cmin lies an optimal therapeutic window, which, because of the dose–response rela- tionship associated with cholinesterase inhibitors, offers the best balance between efﬁcacy and the potential for side effects. The ideal pharmacokinetic proﬁle for a cholinesterase inhibitor treatment would be a smooth, steady delivery of the drug, maintaining plasma levels within this window. One way this may be achieved is by modifying the dosing regimen, as demonstrated in a recent, rando- mised, placebo-controlled trial comparing the efﬁcacy and safety of twice daily (bid) vs. three times daily (tid) rivastigmine capsules (9). By administering the same target daily dose of rivastigmine in smaller, more frequent doses, the Cmax and peak–trough difference in plasma concentration were reduced. This was reﬂected in a lower discontinuation rate because of AEs in the tid group compared with the bid group (10.6% and 16.7%, respectively; placebo = 9.0%). Furthermore, a greater proportion of subjects reached the target dose (12 mg ⁄ day) in the tid group vs. the bid group (60% vs. 43% after the 12-week titration phase) and larger treatment effects were observed for the primary efﬁcacy variables. After 26 weeks, a 0.2- point improvement was observed in the tid group on the cognitive subscale of the Alzheimer’s Disease Assessment Scale, and a 0.1-point improvement on the Clinician’s Interview-Based Impression of Change plus Caregiver Input (vs. a 1.2- and 0.1-point deterioration in the bid group respectively) (9). This suggests that a smoother pharmacokinetic proﬁle is associated not only with improved tolerability, but may also allow more patients to reach higher doses, potentially improving treatment effectiveness. An alternative strategy for reducing Cmax and pro- longing tmax (while maintaining the overall drug expo- sure) is co-administration of rivastigmine with food. This can delay the absorption of the drug from the gut. However, the effect is heavily dependent on the type of food involved, and as such can be unpredict- able. Furthermore, simply reducing Cmax alone does not necessarily improve tolerability. A study evaluating the safety and tolerability of an extended-release (ER) formulation of galantamine showed no advantage of ER capsules vs. conventional capsules (10). The Cmax was reduced with the ER formulation. However, the initial rate of absorption was similar to that seen with conventional capsules, resulting in a similar peak– trough difference of 40 ng ⁄ ml over 24 h. This was reﬂected in a similar incidence of cholinergic AEs (10). The development of a transdermal patch was therefore favoured over an ER formulation for rivastigmine. By providing smooth and continuous delivery of rivastigmine through the skin and directly into the bloodstream, a transdermal patch would lower Cmax and prolong tmax while maintaining drug exposure. As discussed, this could potentially improve tolerability, allow patients easier access to therapeutic doses and optimise the effectiveness of treatment (6). The dosing frequency study, combined with improved patch technology, therefore provided the rationale for the development of a rivastigmine transdermal patch for the treatment of AD. Pharmacokinetic proﬁle of the rivastigmine patch Multilayer matrix patch design Unlike early transdermal patches, which utilised a ‘reservoir’ of the drug dissolved in an adjunct to facilitate drug absorption through the skin (usually alcohol), the rivastigmine transdermal patch uses a modern matrix design. This combines the drug, antioxidants, a polymer mixture that controls the drug delivery rate, and a silicone matrix adhesive to make a single ‘polymeric matrix’ layer. This allows smooth, controlled delivery of the drug via diffusion from the matrix and enables the patches to be kept small, thin and discreet (11). Absorption The efﬁciency and rate of absorption of a drug through the skin is dependent on many biological ª 2009 The Authors Journal compilation ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 799–805