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

Abstract

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 Cmax, AUC0-72 h and AUC0-∞ 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 tmax of huperzine A was 0.76-0.82 h; the AUC0-72 h and Cmax 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.

• Authors: Jing-ying Jia, Qian-hua Zhao, Yun Liu, Yu-zhou Gui, Gang-yi Liu, Da-yuan Zhu, Chen Yu, Zhen Hong
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 34 Issue 7 Pg. 976-82 (Jul 2013) ISSN: 1745-7254 [Electronic] United States
• PMID: 23624756 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• Alkaloids
• Cholinesterase Inhibitors
• Prodrugs
• Sesquiterpenes
• ZT-1 compound
• huperzine A

Topics

• Alkaloids (administration & dosage, adverse effects, pharmacokinetics)
• Alzheimer Disease (drug therapy, metabolism)
• Cholinesterase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Cross-Over Studies
• Double-Blind Method
• Humans
• Male
• Prodrugs (administration & dosage, adverse effects, pharmacokinetics)
• Sesquiterpenes (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Young Adult