Pharmacokinetic Evaluation by Modeling and Simulation Analysis of a Donepezil Patch Formulation in Healthy Male Volunteers.

INTRODUCTION: This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation. METHODS: PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software. RESULTS: A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application. CONCLUSION: PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.

Factors Associated With Deprescribing Acetylcholinesterase Inhibitors in Older Nursing Home Residents With Severe Dementia.

BACKGROUND/OBJECTIVE: Uncertainty regarding benefits and risks associated with acetylcholinesterase inhibitors (AChEIs) in severe dementia means providers do not know if and when to deprescribe. We sought to identify which patient-, provider-, and system-level characteristics are associated with AChEI discontinuation. DESIGN: Analysis of 2015 to 2016 data from Medicare claims, Part D prescriptions, Minimum Data Set (MDS), version 3.0, Area Health Resource File, and Nursing Home Compare. Cox-proportional hazards models with time-varying covariates were used to identify patient-, provider-, and system-level factors associated with AChEI discontinuation (30-day or more gap in supply). SETTING: US Medicare-certified nursing homes (NHs). PARTICIPANTS: Nonskilled NH residents, aged 65 years and older, with severe dementia receiving AChEIs within the first 14 days of an MDS assessment in 2016 (n = 37 106). RESULTS: The sample was primarily white (78.7%), female (75.5%), and aged 80 years or older (77.4%). The most commonly prescribed AChEIs were donepezil (77.8%), followed by transdermal rivastigmine (14.6%). The cumulative incidence of AChEI discontinuation was 29.7% at the end of follow-up (330 days), with mean follow-up times of 194 days for continuous users of AChEIs and 105 days for those who discontinued. Factors associated with increased likelihood of discontinuation were new admission, older age, difficulty being understood, aggressive behavior, poor appetite, weight loss, mechanically altered diet, limited prognosis designation, hospitalization in 90 days prior, and northeastern region. Factors associated with decreased likelihood of discontinuation included memantine use, use of strong anticholinergics, polypharmacy, rurality, and primary care prescriber vs geriatric specialist. CONCLUSION: Among NH residents with severe dementia being treated with AChEIs, the cumulative incidence of AChEI discontinuation was just under 30% at 1 year of follow-up. Our findings provide insight into potential drivers of deprescribing AChEIs, identify system-level barriers to deprescribing, and help to inform covariates that are needed to address potential confounding in studies evaluating the potential risks and benefits associated with deprescribing. J Am Geriatr Soc 67:1871-1879, 2019.