Pharmacokinetics and multi-peak phenomenon analysis of novel anti-Parkinson’s drug FLZ after multi-dose in cynomolgus monkeys

Abstract

1. The novel anti-Parkinson disease drug, FLZ, had a complicated drug absorption and metabolise process reported in single-dose studies. A multi-peak absorption peak phenomenon was found.

2. This study focused on the multi-dose pharmacokinetics (PK) characteristics of FLZ, T1, and T2 in cynomolgus monkeys and raised discussion on its multi-peak absorption situation. Different doses of FLZ ranging from 75 to 300 mg/kg were administered orally to 16 cynomolgus monkeys. The whole treatment period lasted for 42 days with FLZ once a day.

3. The primary metabolites of FLZ were Target1 (T1) and Target2 (T2), which had plasma exposure (calculated as AUC_0–24, day 42) approximately 2 and 10 times higher than the parent drug. The proportion of plasma exposure increase was lower than the proportion of dose increase in FLZ, T1, and T2.

4. Gender influenced its exposure (AUC_0–24) with approximately 3-fold higher in males than females. There was no significant accumulation of T1 and T2. Enterohepatic Circulation (EHC) and gastrointestinal (GI) tract absorption may be involved in the mechanism of multi-peak characteristics.

Keywords:

• FLZ
• anti-Parkinson drug
• MPTP-induced cynomolgus monkey
• multi-dose pharmacokinetics
• multi-peak absorption

Acknowledgements

We express our sincere appreciation to Shijiazhuang Yiling Pharmaceutical Co., Ltd. for their generous funding and invaluable data support, which greatly contributed to the success of this research. Special thanks to all the dedicated staff members involved in the experiments for their hard work and commitment.

Ethical approval

The animal management and protocol for this study received approval from the Institutional Animal Care and Use Committee (IACUC) of Guangxi Nanning Linkson Bio-technology Co., Ltd. (An institution accredited by the international AAALAC organization), the IACUC Number is W00167.

Disclosure statement

The authors report no declarations of interest.

Data availability statement

Data is contained within the article.

Additional information

Funding

This research was funded by Shijiazhuang Yiling Pharmaceutical Co. Ltd. The work was also supported by National High Level Hospital Clinical Research Funding [2022-PUMCH-B-033 and 2022-PUMCH-A-060].