Pharmacokinetics of the rivastigmine patch 801 and physiochemical factors. Lipophilic agents may pass rapidly through the stratum corneum via the lipid-rich intercellular space, whereas hydrophilic agents must dissolve and diffuse through cellular- bound water into the bloodstream (11). The molecu- lar size of the agent is also an important factor in determining the suitability for transdermal delivery; smaller molecules tend to be absorbed faster than larger molecules, with very large molecules such as insulin (5808 Da) being too large to pass through the skin. It has been suggested that any compound with a molecular weight above 500 Da is likely to be unsuitable for transdermal delivery (12). As a small ( 250 Da), lipophilic and hydrophilic molecule, riv- astigmine is chemically well-suited to transdermal delivery. To provide the necessary concentration gradient to drive the diffusion process through the skin, all rivastigmine transdermal patches are loaded with a greater amount of rivastigmine than will be absorbed into the bloodstream. In a study of 51 AD patients, the average amount of rivastigmine absorbed from a patch over a 24-h application period was approximately 50% of the total loading dose. The 5 cm2 patch released 4.6 mg (51% of 9 mg), the 10 cm2 patch released 9.5 mg (53% of 18 mg), the 15 cm2 patch released 13.3 mg (49% of 27 mg) and the 20 cm2 patch released 17.4 mg (48% of 36 mg) (13). Absorption of any remaining rivastigmine following the 24-h application period was shown to occur very slowly (13). Patients should therefore not be at risk of toxic exposure should a new patch be mistakenly applied without prior removal of the previous patch. Once removed, the short elimination half-life (t1 ⁄ 2) of rivastigmine (cap- sule doses = 1.3–1.9 h; 17.4 mg ⁄ 24 h patch = 3.4 h) (13) ensures the rapid reduction of drug levels in the plasma. As a result, even with the continuous delivery provided with the rivastigmine patch, there is little potential for accumulation in the body. Daily pharmacokinetic proﬁle The results from an open-label study of 51 AD patients randomised to rivastigmine patch (4.6–17.4 mg ⁄ 24 h; 5–20 cm2), or capsules (3–12 mg ⁄ day), were used in a compartmental analysis to model rivastigmine plasma levels over a 24-h applica- tion period (Figure 1). Drug exposure was assessed by measuring the area under the curve over a 24-h treatment period (AUC24 h), using a speciﬁc power model (14). The 4.6 mg ⁄ 24 h patch was shown to provide comparable rivastigmine exposure to a 6 mg ⁄ day capsule dose [AUC24 h = 64 and 60 ngÆh ⁄ ml (p = ns) respectively] and the 9.5 mg ⁄ 24 h patch comparable exposure to the highest recommended capsule dose [12 mg ⁄ day; AUC24 h = 166 and 207 ngÆh ⁄ ml (p = ns) respectively]. The 13.3 mg ⁄ 24 h and 17.4 mg ⁄ 24 h patches provide greater rivastigmine exposure than any approved oral dose (AUC24 h = 312 and 474 ngÆh ⁄ ml). All patch doses provided smoother and more con- tinuous delivery of rivastigmine than oral adminis- tration (Figure 1) (15). Both the 4.6 mg ⁄ 24 h and 9.5 mg ⁄ 24 h patches provided signiﬁcantly lower riv- astigmine Cmax and longer tmax (all p < 0.001) vs. capsule doses of comparable exposure: 6 mg ⁄ day (Cmax 3.3 vs. 6.8 ng ⁄ ml; tmax 8.2 vs. 1.2 h) and 12 mg ⁄ day (Cmax 8.7 vs. 21.6 ng ⁄ ml; tmax 8.1 vs. 1.4 h) respectively (15). These results are supported by a separate, non-compartmental, non-adjusted analysis of the same data (13). Similarly, a recent study comparing rivastigmine oral solution (3 mg ⁄ day) with the 9.5 mg ⁄ 24 h patch showed the patch to have a 20% lower Cmax and 14-times longer tmax, with ﬁve-times the drug exposure of the oral solution (Cmax = 5.8 vs. 7.6 ng ⁄ ml; tmax = 14.1 vs. 1.0 h; AUC¥ = 118 vs. 23 ngÆh ⁄ ml respectively) (16). By providing similar drug exposure with a lower maximum concentration and slower absorption rate, the rivastigmine patch may provide similar efﬁcacy to orally administered rivastigmine, with a more favourable tolerability proﬁle. Enzyme inhibition Rivastigmine is distinct from other available cholin- esterase inhibitors (donepezil and galantamine), in that it is a pseudo-irreversible inhibitor of both AChE and BuChE, rather than a rapidly reversible inhibitor of AChE alone. The inhibition of these enzymes in vivo was expected to mirror the plasma concentration proﬁles, with the rivastigmine patch providing steadier and more consistent inhibition than that of oral rivastigmine. AChE has an extre- mely low concentration in the plasma, and as such the enzymatic activity cannot be measured. However, as rivastigmine is a dual inhibitor, the enzymatic activity of BuChE in the plasma may be used as a marker of target enzyme inhibition over time. In a pharmacokinetic study by Lefe`vre et al. (13), a steady reduction in plasma BuChE activity was observed following patch administration. The target dose 9.5 mg ⁄ 24 h patch provided maximum inhibi- tion after 12 h and maintained this for the remain- der of the 24-h application period. In contrast, two distinct peak–troughs in plasma BuChE activity were seen with capsule administration. These results indi- cate that the inhibition of the target enzymes of riv- astigmine follows the pharmacokinetic proﬁle closely, with the patch providing smooth and continuous ª 2009 The Authors Journal compilation ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 799–805