Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of Benfotiamine in Healthy Subjects

作者：Lei Sheng, Wei Cao, Pingping Lin, Wei‐Li Chen, Hongrong Xu, Chunjiu Zhong, Fei Yuan, Hanjing Chen, Hui Li, Chao Liu, Mengjie Yang, Xuening Li · 发表于：Drug Design Development and Therapy · 年份：2021 · DOI：10.2147/dddt.s296197 · 被引用次数：15 · 研究领域：Alkaloids: synthesis and pharmacology、Forensic Toxicology and Drug Analysis、Pharmacovigilance and Adverse Drug Reactions

Purpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials. Methods: Healthy subjects were sequentially enrolled into one of five SAD (150– 1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4– 9, followed by a single morning dose on day 10. Results: In the SAD study, the median time to reach maximum concentration (T max ) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC 0-t ) or maximum observed concentration (C max ) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except C max of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t 1/2 ) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on C max (Rac, Cmax ) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results wer...