Jianye Wen

Absorption, Distribution and Excretion Pattern of Oral and Transdermal Donepezil Hydrochloride after Single and Repeated Administration to the Rat

Donepezil hydrochloride formulated in a transdermal patch for weekly administration is an alternative to the approved daily oral tablet. Transdermal delivery has a locally high concentration at the application site causing potential safety issues. To assess the skin exposure for safety evaluation, studies were performed comparing the donepezil transdermal patch with an oral donepezil dose previously tested in a carcinogenicity study, in which no test article-induced tumors were found. Quantitative Whole Body Autoradiography (QWBA) comparison in Long-Evans rats administered 14C-donepezil either as single oral dose (30 mg/kg) or a 24-hour transdermal patch (~60 mg/kg) revealed similar organ distribution, including skin. Pigmented tissue, namely, skin and eye showed sustained labeling over 7-10 days, suggesting melanin binding. Subsequently, a 14C-donepezil study in Long-Evans rats comparing seven daily oral doses (10-30 mg/kg) with a seven-day transdermal patch (~40 mg/kg) again revealed similar tissue distributions between the two delivery methods, however, skin not directly exposed to the transdermal patch had less label as compared to both unpigmented and pigmented skin after oral dosing. Similarly, eye concentrations generally had higher label after oral dosing as compared to the transdermal administration. Upon patch removal, the non-viable stratum corneum under the dose-site contained the majority of the label with the underlying skin layers returning to baseline levels within 5 and 7 days for unpigmented and pigmented skin, respectively, illustrating dermal clearance. Skin structures were comparably labeled after oral and transdermal administration, as evidenced by microautoradioagraphy.

Dried Blood Spot Analysis of Donepezil in Support of a GLP 3-Month Dose-Range Finding Study in Rats

Donepezil hydrochloride is a reversible acetyl cholinesterase inhibitor approved for Alzheimer disease treatment. As an alternate therapy, a donepezil hydrochloride transdermal patch is in development. Recommended nonclinical safety studies include a 3-month Good Laboratory Practice (GLP) dose-range finding (DRF) study prior to conducting the 2-year dermal carcinogenicity study in rats. Demonstration of systemic exposure is necessary to interpret the in vivo data. Previous nonclinical reports supporting oral dosing have utilized liquid chromatography tandem mass spectrometry (LC/MS/MS) to quantify donepezil concentrations in plasma. Smaller species with limited blood volumes do not allow serial sampling to derive the full pharmacokinetic profile from a single animal. Therefore, the option of another analytical method requiring decreased sample volumes is desirable as it would decrease the required number of animals while obtaining the complete profile. The dried blood spot (DBS) technique allows drug level measurement from a few microliters; however, the method is still not widely utilized in GLP studies. Because donepezil plasma levels are known by the oral route, DBS was used to bridge the previous oral data and to support a 13-week GLP DRF study for repeated topical application in rats, comparing oral administration with 4 topical formulations. The DBS method was validated and demonstrated robustness and reproducibility for application to the DRF study. The assay results were comparable to a previously reported plasma LC/MS/MS assay-derived pharmacokinetic profile and provided justification for selection of the topical formulation and dose levels for the subsequent dermal carcinogenicity study.