Pharmacokinetics of the rivastigmine patch 803 A B Figure 2 (A) Mean drug exposure (area under curve) following a single 24-h application of the 9.5 mg ⁄ 24 h rivastigmine patch to the upper back, chest, abdomen, thigh or upper arm of 40 healthy subjects. (B) Recommended application sites reduce the potential for skin irritation, the patch should be alternated daily between sites on the right and the left side of the body. Metabolism and bioavailability Rivastigmine is rapidly and extensively metabolised to the inactive NAP226-90 metabolite by its target enzymes (AChE and BuChE), with little or no inter- action with hepatic cytochrome P450 isoenzymes (18). However, a small amount of ﬁrst-pass metabo- lism of orally administered rivastigmine may still occur via peripheral cholinesterases in the gut. This effect has been demonstrated in previous pharmaco- kinetic studies by assessing the ratio of NAP226-90 to rivastigmine following transdermal patch or oral (capsule or solution) administration (13,16). The ratio was shown to be considerably lower following transdermal treatment (0.60–0.72) (13,16) than both capsule (1.10–3.15) (13) and oral solution (3.49) (16) treatment. This indicates that rivastigmine administered transdermally bypasses the phase I metabolism, thereby increasing the systemic bioavail- ability of the drug. Consequently, the 9.5 mg ⁄ 24 h rivastigmine patch (10 cm2, AUC24 h = 166 ngÆh ⁄ ml) may provide comparable effectiveness to the highest doses of capsules (12 mg ⁄ day, AUC24 h = 207 ngÆh ⁄ ml), despite having a numerically lower AUC24 h. Clinical effects with transdermal dosing One of the major obstacles to the effective treatment of AD with oral cholinesterase inhibitors has been tolerability, which can prevent many patients from reaching efﬁcacious therapeutic doses in clinical practice. Until recently, all cholinesterase inhibitors were administered orally, but the newly developed rivastigmine patch appears to overcome this tolera- bility obstacle by employing a different dosing route and may offer a substantial clinical advantage. Modelling analyses adjusting for baseline demo- graphic factors demonstrated that the 9.5 mg ⁄ 24 h patch (10 cm2) provides comparable exposure, and therefore potentially similar efﬁcacy, to the highest doses of rivastigmine capsules (12 mg ⁄ day). The pharmacokinetic proﬁle, with a reduced Cmax and prolonged tmax, also predicts an improved tolerability proﬁle vs. conventional rivastigmine capsule adminis- tration. These hypotheses are supported by results from the landmark Investigation of transDermal Exelon in ALzheimer’s disease trial (IDEAL). This was a randomised, double-blind, double-dummy, placebo- controlled trial to investigate the efﬁcacy and tolera- bility of the rivastigmine patch (4.6–17.4 mg ⁄ 24 h) vs. capsules (3–12 mg ⁄ day) in 1195 AD patients (19). Patients randomised to patch treatment were started on the 4.6 mg ⁄ 24 h patch and titrated in a single step to the recommended 9.5 mg ⁄ 24 h patch. During the 24-h application period, patients were able to pursue all normal activities, including washing and bathing. The trial was also conducted in countries with varying climates, including some hot and humid regions (e.g. Guatemala, Venezuela). The 9.5 mg ⁄ 24 h patch provided similar efﬁcacy to the highest doses of capsules (12 mg ⁄ day) on vari- ous outcome measures (Table 1), with three times fewer reports of nausea and vomiting (7.2% vs. 23.1% and 6.2% vs. 17.0% respectively; Table 1) (19). This supports the rationale for the patch that a smoother pharmacokinetic proﬁle would yield fewer cholinergically mediated AEs while maintaining ther- apeutic concentrations. Similar efﬁcacy between the 9.5 mg ⁄ 24 h patch and 12 mg ⁄ day capsule groups, despite the patch providing slightly less drug, dem- onstrates the advantage with transdermal delivery of the avoidance of ﬁrst pass metabolism by peripheral cholinesterases in the gut. The efﬁcacy of the 4.6 mg ⁄ 24 h patch was not assessed in the IDEAL trial, however pharmacokinetic ª 2009 The Authors Journal compilation ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 799–805