First-in-Human Safety, Tolerability and Pharmacokinetics of a Novel Drug
with Therapeutic Potential for Vascular Dementia, Naoqingzhiming Tablet:
Results from Single Ascending Doses studies in Healthy Chinese Subjects
Abstract
Purpose: The primary aim of this study was to evaluate the safety,
tolerability and pharmacokinetics of single ascending doses of
Naoqingzhiming tablet after oral administration in healthy Chinese
subjects. Methods: This study adopted randomized, double-blind,
placebo-controlled dose ascending trial design. Healthy Chinese subjects
were sequentially enrolled into one of six cohorts (180, 360, 720, 1080,
1620, 2160 mg). Blood samples were collected at specified time
intervals, and the plasma concentrations of echinacoside were determined
by a validated LC–MS/MS method. PK parameters were estimated via
non-compartmental methods. Tolerability was evaluated by monitoring
adverse events (AEs), physical examination, laboratory assays, vital
signs, and 12-lead ECG. Results: The single ascending dose of
Naoqingzhiming tablet (180-2160 mg) were well tolerated in all enrolled
subjects, without serious adverse events and adverse events leading to
withdrawal from the study. After single-dose administration of
Naoqingzhiming tablet, echinacoside was absorbed with a Tmax at
1.25-1.75 h and declined with a t1/2 of 2.42-3.33 h. However, the
proportionality coefficients for Cmax, AUC0-t and AUC0-∞ of echinacoside
were not fully contained in the pre-defined 90 % CI criterion
(0.91-1.09). As a result, the dose proportionality could not be
concluded statistically within the dosage range of this study.
Conclusion: Our study provided the initial safety, tolerability and
pharmacokinetic profiles of Naoqingzhiming tablet, and could enable
further clinical development in vascular dementia patients.