Transdermal Rivastigmine Delivery for Alzheimer Disease: Amenability of Exposure Predictions of Rivastigmine and Metabolite, NAP226-90, by Linear Regression Model Using Limited Samples

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Although an optimized delivery of rivastigmine for management of Alzhiemer disease (AD) is provided by the transdermal patch, it is critical to establish a limited sampling strategy for the measurement of exposure of rivastigmine/NAP226-90.


The relationship Cmax versus AUC0–24h for rivastigmine/NAP226-90 was established by regression models. The derived regression equations enabled the prediction AUC0–24h for rivastigmine and NAP226-90. Models were evaluated using statistical criteria. Mixed model was used to predict AUC0–24h for rivastigmine/NAP226-90 from time points such as 8 (C8h), 12 (C12h), and 18 (C18h) hours.


Excellent correlation was established for between Cmax and AUC0–24h for rivastigmine and NAP226-90. AUC0–24h predictions of either rivastigmine or NAP226-90 were within 0.8- to 1.25-fold difference. The RMSE in the AUC0–24h predictions ranged from 17.6% to 21.9%, and the R2 for prediction were greater than 0.96 for both rivastigmine and NAP226-90. Use of mixed model for C8h, C12h, and C18h resulted in AUC0–24h within 1.5-fold difference for rivastigmine or NAP226-90.


Cmax of rivastigmine and NAP226-90 was highly correlated with the corresponding AUC0–24h values confirming the role of a time point closer to Cmax for an effective AUC measurement of rivastigmine or the metabolite.

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