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

Abstract

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. 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. The primary metabolites of FLZ were Target1 (T1) and Target2 (T2), which had plasma exposure (calculated as AUC0–24, 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. Gender influenced its exposure (AUC0–24) 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.