120: Effect of Herbal Medicines on the Pharmacokinetics of Donepezil

Statement of Purpose, Innovation or Hypothesis: Donepezil is a reversible acetylcholinesterase inhibitor used for the treatment of Alzheimer’s disease (AD) [1]. Herbal medicines are being utilized for symptom management in patients with AD, often concurrently with donepezil. However, it remains unclear whether there are interactions between donepezil and herbal medicines when administered together. Therefore, this study aimed to investigate the pharmacokinetic (PK) interaction and safety of donepezil (D: Aricept^® 5 mg) when co-administered with Gamisoyosan (A1), Banhasasim-tang (A2), Ojeoksan (A3), or Bojungikki-tang (A4) in healthy adults.

Description of Methods & Materials: This study was conducted in healthy subjects by using an open-label, multiple-dose, one sequence, three-period crossover design, divided into four parts corresponding to the number of herbal medicines (A1, A2, A3, and A4). In the first period of part 1, each subject received a single oral administration of donepezil, followed by a 14-day wash-out period. In the second period of part 1, subjects received oral administration of A1 once. After the second period, the third period was started without a wash-out period. In the third period of part 1, subjects received co-administration of donepezil once daily and A1 three times daily from day 1 to day 14. On day 15, subjects received co-administration of donepezil and A1 orally once. The same procedure was followed for the other parts, with subjects assigned to different herbal medicines (A2, A3, and A4). The primary PK endpoints of donepezil were C_max,ss and AUC_tau,ss. The C_max,ss and AUC_tau,ss of the donepezil monotherapy were determined using a nonparametric superposition method. PK analyses were conducted using WinNonlin^® (ver. 8.3; Certara, NJ, USA).

Data & Results: A total of 35 subjects were enrolled in the study, divided into four parts: part 1 (n=9), part 2 (n=9), part 3 (n=9), and part 4 (n=8). Of these, 34 subjects completed the study. The geometric mean ratio and corresponding 90% confidence intervals for the co-administration of donepezil with A1, A2, A3, and A4 to donepezil for C_max,ss and AUC_tau,ss were as follows: for A1, 1.57 (1.37­­–1.80) and 1.48 (1.24–1.77); for A2, 1.80 (1.43–2.27) and 1.73 (1.32–2.26); for A3, 1.56 (1.31–1.85) and 1.52 (1.25–1.85); and for A4, 1.90 (1.42–2.54) and 1.72 (1.22–2.42). For safety, a total of 19 cases of adverse events were reported, with eight cases being classified as adverse drug reactions, occurring only in part 1 (headache and nausea) whereas no adverse drug reaction was reported in other parts.

Interpretation, Conclusion or Significance: The co-administration of donepezil with A1, A2, A3, and A4 resulted in a 1.56– to 1.90–fold increase in the C_max,ss of donepezil and a 1.48- to 1.73-fold increase in AUC_tau,ss of donepezil, respectively. In terms of safety, no serious adverse events were reported, and all adverse events were resolved without sequelae. Furthermore, the co-administration of donepezil and herbal medicines appeared to have a relatively good safety profile.

Disclosures: All of the authors declare that they have no other relevant affiliations or financial involvement with any organization or entity that has a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Citations/References: 1. Kumar, A., Gupta, V., & Sharma, S. (2023, August 17). Donepezil. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK513257/. 2. National Development Institute of Korean Medicine, 2017 Survey on the Utilization of Traditional Korean Medicine and the Status of Herbal Medicine Consumption. 2018.

Additional Information/Authors: This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HF20C0212).