Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease

• Published in: Acta pharmacologica Sinica Vol. 34; no. 7; pp. 976 - 982
• Main Authors: Jia, Jing-ying, Zhao, Qian-hua, Liu, Yun, Gui, Yu-zhou, Liu, Gang-yi, Zhu, Da-yuan, Yu, Chen, Hong, Zhen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2013; Nature Publishing Group
• Subjects: Alkaloids - administration & dosage; Alkaloids - adverse effects; Alkaloids - pharmacokinetics; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Biomedical and Life Sciences; Biomedicine; Cholinesterase Inhibitors - administration & dosage; Cholinesterase Inhibitors - adverse effects; Cholinesterase Inhibitors - pharmacokinetics; Cross-Over Studies; Double-Blind Method; Humans; Huperzia; Immunology; Internal Medicine; Male; Medical Microbiology; Original; original-article; Pharmacology/Toxicology; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - pharmacokinetics; Sesquiterpenes - administration & dosage; Sesquiterpenes - adverse effects; Sesquiterpenes - pharmacokinetics; Treatment Outcome; Vaccine; Young Adult; prodrug; ZT-1; huperzine A; pharmacokinetics; drug tolerance; Alzheimer's disease; AChE inhibitor
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/aps.2013.7

Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. Methods: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po ) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po ) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po ). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including C max , AUC 0–72 h and AUC 0–∞ were calculated. Tolerance assessments were conducted throughout the study. Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean t max of huperzine A was 0.76–0.82 h; the AUC 0–72 h and C max of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. Conclusion: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.