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

Authors Sheng L, Cao W, Lin P, Chen W, Xu H, Zhong C, Yuan F, Chen H, Li H, Liu C, Yang M, Li X

Received 23 December 2020

Accepted for publication 19 February 2021

Published 9 March 2021 Volume 2021:15 Pages 1101—1110


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Anastasios Lymperopoulos

Lei Sheng,1,* Wei Cao,2,* Pingping Lin,3 Weili Chen,1 Hongrong Xu,1 Chunjiu Zhong,4 Fei Yuan,1 Hanjing Chen,1 Hui Li,1 Chao Liu,1 Mengjie Yang,1 Xuening Li1

1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Rixin Biotechnology Co., Ltd, Shanghai, 200237, People’s Republic of China; 3Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, Shandong, 266071, People’s Republic of China; 4Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xuening Li
Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, 200032, People’s Republic of China
Tel +86 21 3158 7860
Fax +86 21 6443 7963
Email [email protected]

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 (Tmax) 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 (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC.
Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.

Keywords: Alzheimer’s disease, benfotiamine, thiamine, thiamine diphosphate, pharmacokinetics

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