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

Purpose: 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. Methods: The relationship C-max versus AUC(0-24h) for rivastigmine/NAP226-90 was established by regression models. The derived regression equations enabled the prediction AUC(0-24h) for rivastigmine and NAP226-90. Models were evaluated using statistical criteria. Mixed model was used to predict AUC(0-24h) for rivastigmine/NAP226-90 from time points such as 8 (C-8h), 12 (C-12h), and 18 (C-18h) hours. Results: Excellent correlation was established for between C-max and AUC(0-24h) for rivastigmine and NAP226-90. AUC(0-24h) predictions of either rivastigmine or NAP226-90 were within 0.8- to 1.25-fold difference. The RMSE in the AUC(0-24h) predictions ranged from 17.6% to 21.9%, and the R-2 for prediction were greater than 0.96 for both rivastigmine and NAP226-90. Use of mixed model for C-8h, C-12h, and C(18)h resulted in AUC(0-24h) within 1.5-fold difference for rivastigmine or NAP226-90. Conclusions: C-max of rivastigmine and NAP226-90 was highly correlatedwith the corresponding AUC(0-24h) values confirming the role of a time point closer to C-max for an effective AUC measurement of rivastigmine or the metabolite.